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Anti-Cancer Agents in Medicinal Chemistry, XXXX, XX, 0-0 1

REVIEW ARTICLE

Recent Prospectives of Cellular Signaling Role for Mammary Gland Carcinogenesis

Monu Kumar Kashyap1,*, Sikma Roy1, Shiwani Jaiswal1, Shweta Verma1, Siddharth Srivastava1, Amit Kumar
Nigam1, Awadhesh Kumar1, Bandana Singh1, Ved Prakash Tiwari1, Mahima Mahima4, Akash Ved2,*, Karuna
S Shukla1 Namrata Singh3

1
Goel Institute of Pharmaceutical Sciences, Lucknow, UP, India; 2Faculty of Pharmacy, Dr. A. P. J. Abdul Kalam Technical
University, Lucknow, UP, India; 3Department of Pharmaceutical Sciences, Lucknow University, Lucknow, UP, India; 4Department of
Pharmaceutical Sciences, Dr Shakuntala Misra National Rehabilitation University, Lucknow, UP, India

Abstract: In women globally, breast cancer ranks as the second most frequent cause of cancer-related deaths,
making up about 25% of female cancer cases, which is pretty standard in affluent countries. Breast cancer is
divided into subtypes based on aggressive, genetic and stage. The precise cause of the problem is still unknown.
However, the following significant risk factors have been found: sex, age, heredity, not having children, breast-
feeding, elevated hormone levels, and personal lifestyle. The presence or lack of three nuclear receptors ER, PR,
and HER2/ERBB2 (triple negative) and the amplification of the HER2/ErbB2 gene are the clinical criteria used to
classify breast cancer. Chemotherapy is still the cornerstone of treatment for triple-negative breast cancer
(TNBC), even. If, for the first two groups of patients,receptor-specific therapy is used. The most often prescribed
ARTICLE HISTORY chemotherapy agents for the treatment of breast cancer include doxorubicin (DOX), curcumin paclitaxel (PTX),
docetaxel (DCX), thioridazine (THZ), disulfiram (DSF), and camptothecin (CPT). Monoclonal antibodies (mAbs)
Received: June 10, 2024
Revised: October 06, 2024 were used in antibody-drug conjugates (ADCs) to bind tumor-associated target antigens selectively and deliver
Accepted: October 09, 2024
very effective cytotoxic agents. According to recent research, synthetic derivatives effectively combat both MCF-
DOI: 7 and breast cancer cell lines that are resistant to many drugs. This review provides a wealth of information on the
10.2174/0118715206319933241104100736
mechanism of action of synthetic derivatives on multidrug-resistant cell lines. This review includes information
about how synthetic derivatives affect cancer cells that have developed multidrug resistance during chemothera-
py. These mechanisms have been linked to factors such as increased drug efflux, genetic factors, growth factors,
increased DNA repair capacity, and elevated xenobiotic metabolism. Because of this, more research is necessary
to learn more about the effectiveness of synthetic derivatives against breast cancer and cell lines that are resistant
to several drugs. This review aims to find recent prospects of various types of cellular signaling pathways
(JAK/STAT, Akt, MAPK, etc.) involved in the progression of breast cancer disorder, and we also study different
synthetic and natural drugs that are applied for treating breast cancer.

Keywords: Breast cancer, HER2/ERBB2, multidrug resistance, PDGF, WNT signaling, TNBC.

1. INTRODUCTION factors have been found: sex, age, heredity, not having children,
breastfeeding, elevated hormone levels, and personal lifestyle [4,
Breast cancer is the most critical disorder in women's breast 5]. Lung cancer is the second most prevalent malignancy among
tissue. Breast cancer ranks fifth globally in terms of cancer-related newly diagnosed female patients after breast cancer. Currently,
deaths, accounting for 10.4% of all cancer incidence and being the available treatments for breast cancer include radiation, chemother-
most common type of non-skin cancer among women [1]. Accord- apy, surgery, and targeting traditional breast cancer markers. After
ing to the report, there are approximately 2.3 million new cases of surgery, 80% of women with initial breast cancer go on to live for
breast cancer globally, which ranks it as the fifth most prevalent ten years or more [6]. With 450,000 yearly fatalities worldwide,
cause of cancer-related death and one of the most often diagnosed breast cancer is the most frequent invasive malignancy in women
cancers. With 2.26 million cases worldwide [2]. With 2.26 million and the second most significant cause of cancer-related death in
cases worldwide, breast cancer is the most common malignancy women after lung cancer [7]. Breast cancer can be classified as
among women to receive a diagnosis [3]. In the US, 29% of all new invasive or in situ, with the former being more readily treatable.
cancer cases in women are anticipated to be related to breast cancer Invasive breast cancer is a significant isssue, incredibly invasive
alone. Breast cancer is a type of tumor that arises from breast tissue, ductal carcinoma, which accounts for 80% of all invasive breast
usually from the lobules that provide milk to the ducts or the inner cancer. The presence or lack of three nuclear receptors ER, PR, and
lining of the ducts. Breast cancer is classified into subtypes based HER2/ERBB2 (triple negative) and the amplification of the
on aggressive, genetic makeup, and stage. The precise cause of the HER2/ErbB2 gene are the clinical criteria used to classify breast
problem is still unknown. However, the following significant risk cancer. Chemotherapy is still the cornerstone of treatment for triple-
negative breast cancer (TNBC), even. If for the first two groups of
*Address correspondence to these authors at the Goel Institute of Pharma- patients, receptor-specific therapy is used [8, 9].
ceutical Sciences, Lucknow, UP, India; Breast cancer can be classified as either invasive or in situ, with
E-mail: monukumarkashyap95@gmail.com
invasive types being more challenging to treat. Invasive breast can-
Faculty of Pharmacy, Dr. A. P. J. Abdul Kalam Technical University, Luck-
now, UP, India; E-mail: akashved@gmail.com
cer, particularly invasive ductal carcinoma, which makes up 80% of

1871-5206/XX $65.00+.00 © XXXX Bentham Science Publishers

2 Anti-Cancer Agents in Medicinal Chemistry, XXXX, Vol. XX, No. XX Kashyap et al.

all invasive cases, poses a significant concern. The nuclear – ER, colonization. PDGF stimulates pro-metastatic signals in brain peri-
PR, and HER2/ERBB2, as well as the overexpression of the cytes when it binds to its receptor PDGF-R, releasing ECM proteins
HER2/ErB2 gene, are used in symptomatic breast cancer diagnosis. and insulin-like growth. Several components and signaling path-
The primary method of care for triple negative breast cancer ways are involved in the spread of breast cancer to the brain. The
(TNBC) is still chemotherapy. Recently, antibody drug conjugates primary tumor, breast cancer, separates from its original place dur-
(ADCs) have been used in cancer treatment to deliver powerful ing metastasis and migrates and invades blood circulation before
cytotoxic medicines to tumor-associated antigens with specificity extravasating past the blood-brain barrier and establishing cancer in
using monoclonal antibodies (mAbs). Various nanoparticles, such the brain (brain tropism).
as polymeric nanomicelles, polymer drug conjugates, liposomes,
and inorganic nanoparticles, have been created as tumor-targeting 2.2. Focal Adhesion Kinase (FAK) Pathway
carriers for the selective administration of these medications in
order to solve some of their disadvantages as well [10]. In addition to acting as the primary mediator of integrin signal-
ing, FAK is a nonreceptor tyrosine kinase that is involved in cell
Multidrug resistance (MDR), which can result in tumor relapse signaling by a variety of extracellular stimuli, such as growth fac-
and therapeutic failure, is a significant challenge in the treatment of tor, G-protein coupled receptor agonists, cytokines, and other in-
breast cancer, in addition to metastasis. A novel class of antihormo- flammatory mediators [13]. Accumulating evidence demonstrated
nal drugs called antiprogestins may prove helpful in the manage- that FAK gene is amplified and overexpressed in a significant frac-
ment of Cancer. Mifepristone (RU486) is now accessible for clini- tion of BC tissue, confirming the link between FAK and breast
cal trials and preclinical research. Mifepristone possesses anti- cancers. Interestingly, FAK also stimulates angiogenesis, cell mi-
glucocorticoid characteristics in addition to its anti-progestational gration, and invasion in the BBB following interaction with PI3K
effects. Mifepristone has additional uses besides being a contracep- by generating the FAK-beta4 integrin complex, increasing FAK and
tive pill or an anti-glucocorticoid for treating disorders associated beta4 integrin-positive cells [14]. A differential gene expression
with excessive corticosteroid production [11]. It can also limit the study in BCBM identified genes associated with the focal adhesion
growth of many tumor cell types. We previously observed that tu- pathway and PI3K/AKT [15]. Connexin 43 and LAMNA4 are also
mor growth was inhibited by 40-50% at different dosages of the involved in the FAK pathway in BCBM. In BCBM, the FAK-NF-
progestin megestrol acetate and 80-90% to varying dosages of the beta signaling pathway is a desirable target for chemotherapy. Re-
antiprogestin mifepristone. Pituitary-ovarian stimulation that led to searchers have investigated the chronological event in mice models
undesirable endocrine effects (high levels of prolactin and plasma of BC with brain metastasis enabled by precise immunofluores-
steroid hormone) was not enough to prevent this tumor from inhib- cence microscopy to uncover novel possible molecular targets in
iting. It has also been reported that postmenopausal patients with metastatic cancer [16, 17]. As the metastasis developed, epithelial
metastatic breast cancer can experience growth-inhibitory effects cell markers and focal adhesion kinase signaling followed in the BC
from a single, long-term mifepristone treatment. Peripheral andro- cells. Changes in cytoskeletal-associated signaling pathways related
gen conversion from hyperstimulated adrenals resulted in undesira- to cell invasion, adhesion, and migration are responsible for devel-
ble side effects (such as elevated plasma estradiol concentration) in oping brain metastases [18, 19].
addition to these inhibitory effects. Thus, studies were conducted to
examine the effects of combined treatment with either LHRH- 2.3. DNA Repair Pathway
agonist (bulletin or Zoladex) to lower estradiol secretion or mife-
pristone (to block the pgR) and Tamoxifen (to block the ER). BC cells often spread to the brain, producing a neuro-
inflammatory milieu. We still don't know what chemical mecha-
2. VARIOUS ROLES OF MOLECULAR SIGNALING nism makes colonization easier. According to one study, in ad-
INVOLVED IN BREAST CANCER vanced HER2+ve BC patients, RAD51-a crucial protein involved in
homologous recombination-mediated single –and double-strand
2.1. Extra Cellular Matrix (ECM) –Receptor Signaling DNA repair-is the early molecular predictor of brain metastasis
[20]. Chemoresistance is also linked to aberrant RAD51 expression.
ECM-receptor interactions are frequently associated with up-
The homologous recombination deficit scores of BC original tu-
regulated and gene-enriched signalling pathways. It is commonly
mors were compared with those of their corresponding brain meta-
known that ECM has a role in tumour shedding, adhesion, disinte-
static counterparts [21, 22]. Researchers discovered that brain me-
gration, motility, and hyperplasia in various malignancies. When
tastases were more common in individuals with homology-directed
BC cells invade the brain parenchyma during BCBM, they acquire
repair (HRD) mutations and that PARP-1 inhibitory chemotherapy
markers of mesenchymal origin and lose markers of epithelial cell
may be helpful for BC patients with brain metastases. The PARP-1
origin [12]. Vimentin is carried by BC cells that invade brain pa-
enzyme is essential for DNA repair because it detects damage to
renchyma cells, and the quantity of vimentin-positive cells rises
cells ' DNA. Inhibitors of PARP-1 are fatal to Cancerous cells and
increasing cancer invasion. But as soon as they settle in the brain,
offer medical benefits [23, 24]. An important inhibitor of DNA
the mesenchymal cells vanish and are replaced by epithelial mark-
double-strand break repair, LRRC31, was found to be working as a
ers. ZNF827 is a master regulator that connects these processes
tumor suppressor gene in the MDA-MB-231 BCE cell line using a
during EMT in brain development and BC metastasis. This suggests
genome-wide CRISPR screen. Additionally, they demonstrated that
that the splicing program and the epigenetic landscape interact in a
LRR31 could be utilized as nanoparticles to increase the suscepti-
way that has never been seen before in controlling EMT. As brain
bility of breast-to-brain metastatic mouse models to radiation by
metastasis advances over time, chemicals engaged in crosstalk,
disrupting the ATR-MSH2-PKC signaling axis [25]. H2AX, a DNA
molecular pathways linked in alteration to the brain’s vascular
repair marker, has higher mRNA expression in brain metastat-
structure, and colonization by BC cells in the hippocampus of BC
ic lesions than in initial breast cancer and is related to poor patient
mice models have all been found recently. Over time, there was an
survival, according to the publicly available TGCA dataset of BC
increase in the quantity of PDGF-beta and ki-67-positive cells near
brain metastasis [26, 27].
blood arteries in the brain’s hippocampus. Additionally, Ki-67 is a
predictive marker that affects TNBC BC and HER2+ve patients
2.4. Wnt and Notch Pathways
‘survival periods. Growth factor PDGF-beta is often overexpressed
in gliomas and promotes dedifferentiation and proliferation of cells. The Wnt and Notch signaling pathways are cell signaling path-
A potential prognostic factor for brain metastases may be PDGF- ways that have been preserved throughout evolution. They play a
beta. In the case of TNBC, PDGF-beta is essential for brain cell crucial role in cancer development and are involved in angiogene-
Recent Prospectives of Cellular Signaling Role for Mammary Gland Anti-Cancer Agents in Medicinal Chemistry, XXXX, Vol. XX, No. XX 3

Fig. (1). Many elements and signaling pathways are involved in the brain metastases of breast cancer: The primary tumor (breast cancer) separates from its
original site during metastasis, migrates and invades blood circulation, and then spreads via the blood-brain barrier to Form tumors in the brain (brain tropism).
This process involves several variables and signaling pathways, as shown. (A higher resolution / colour version of this figure is available in the electronic copy
of the article).

sis, CSC maintenance, tumor immunity, and tumor growth when percentages of pCR achieved [34]. The prognosis for pCR in
activated abnormally [28, 29]. Wnt signaling pathways participate HR/HER2+ cancers was statistically significant in a recent meta-
in overrepresentation in primary breast cancer that spreads to the analysis by Von Minckwitz and colleagues, which included seven
brain and basal-like subtype of BC. The brain metastases of basal- randomized neoadjuvant trials [35].
like and other BC subtypes are significant sites for WNT signaling, Furthermore, patients with HER2+ non-luminal tumors had a
which is not canteen-dependent and is most likely mediated by higher DFS. They more often obtained pCR than those with luminal
ROR1-2 [30]. Moreover, early metastasis is predicted by high B HER2+ disease after chemotherapy and trastuzumab—current
ROR2 expression. Notch signaling in nearby cells can be triggered HER2+ illness neoadjuvant clinical trials [36, 37]. In-breast pCR
by the expression of Notch ligands on the cell surface, such as del- were consistently greater in HR in NeoALTTO than in HR+ disease
ta,-like, and jagged ligands (DLL1, DLL3, DLL4, JAG1, and treated with trastuzumab, lapatinib, or both in combination. The
JAG2) [31]. This can lead to the Notch intracellular domain correlation between enhanced EFS and pCR attaintment suggests
(NICDNICD's interaction with transcriptional regulators) creating that these results may have predictive significance [38]. Again, in
Notch gene expression, professional regulators. These profiles gov- the Neosphere trials, in the breast, pCR was higher in HR 63.2%
ern essential decisions about the fate of cells, including survival, disease as opposed to HR +26% in both the chemo-free dual HER2
cell cycle progression, and differentiation [32]. blockade arm and the docetaxel-trastuzumab-pertuzumab arm. In
any case, a molecular subtyping investigation was carried out on
2.5. Therapeutic Role of HER2 and ER Pathways tumor samples before and after systemic therapy, enabling the clin-
ical HER2+ tumor to be classified into each of the four primary
Research conducted in the neo-adjuvant context revealed a
intrinsic subtypes. Interestingly, the HR2-enriched/clinical HER2+
relationship between the activity of anti-HER2 treatments and HR
status. Regardless of HR status, the CT neo-BC pooled analysis, subtype 69% of the response had higher in–breast pCR rates [12,
which included 12 worldwide neo-adjuvant trials, amply confirmed 39].
a correlation between PCR and long-term outcomes in HER2+ BC, Numerous studies in an adjuvant situation showed that
albeit with a more robust connection for the HR subgroup [33]. HR+/HER2+BC patients had worse outcomes than HR+/HER2
Compared to HR-/HER2+ trastuzumab untreated or trast+ and individuals who had HT. In any case, while some research failed to
HR/HER2+ not getting trastuzumab, HR-/HER2+ cancer receiving provide comparable results, others suggest tamoxifen treatment
trastuzumab were the subgroup with the better results after PCR. may have little benefit or be harmful to patients [12]. Furthermore,
Furthermore, of all the BC subtypes and, more precisely, of all the the effectiveness of trastuzumab treatment appeared to be more
HER2+ BC subgroups (HR HER2 + trust + 50.3% PCR vs. HR + pronounced in the first years of follow-up for the HR cohort and
HER2 + trast+ 30.9% PCR vs. HRER2 + trast 30.2% pCR vs HR + more consistent over time for the HR+ cohort, taking into account a
HER2 + trast18.3% pCR), HRHER2+ trast+ disease had the highest different pattern of relapse [40, 41]. Adjuvant trastuzumab in-
4 Anti-Cancer Agents in Medicinal Chemistry, XXXX, Vol. XX, No. XX Kashyap et al.

creased both recurrence-free survival and breast cancer-specific significance in breast cancer patients. In breast cancer, the PI3KCB
survival when combined with chemotherapy in another relatively submission is essential for promoting carcinogenesis, invasiveness,
recent retrospective study about early HR+/HER2+ BC. However, and cell proliferation. G protein-coupled receptors may mediate the
the impact of BCSS on tumors that expressed PgR and ER in over activation of PI3KCB in Cancer. Specifically, the first report of a
30% of cells was not statistically significant. Additionally, adjuvant mutation in the PI3KCB helical domain was made in a patient with
trastuzumab did not significantly improve either objective in tumors breast cancer who is HER2-positive. By improving PI3KCB's base-
where ER and PgR were overexpressed in more than 50% of cells. line interaction with membranes, E633K can raise the level of
Different recurrence patterns were also noted for lower overex- PI3KCB activation. It has been demonstrated that in HER2-
pressing and more significant overexpressing HR tumors: the latter amplified breast tumors treated with PI3KCB, PIP3 buildup and
exhibited a low and stable risk throughout the first five years, fol- AKT reactivation occur. In HER2-amplified and PIK3CA mutant
lowed by a late increase beyond the five-year mark with a negligi- breast tumors, concurrent inhibition of PI3KCB results in increased
ble trastuzumab effect [42]. antitumor efficaciousness when treated with a PI3KCA-specific
inhibitor [46].
2.6. Molecular Targeting Role of PI3K/AKT/mTOR Signaling
Pathway in Breast Cancer 2.7. Cytokine/JAK/STAT Role in Breast Cancer
A PI3/Akt/mTOR cell signaling system controls immune re- Pleiotropic, secreted proteins ranging in size from 15 to 20
sponse, mortality, growth, proliferation, survival, and metabolism. kDa, known as cytokines, are involved in a wide range of inflam-
Numerous illnesses and conditions, including vascular disorders, matory and immune responses frequently misdirected in Cancer.
Parkinson's disease, and tuberous sclerosis, have also been linked to Numerous cytokines, such as interleukin-6 (IL-6), can have pro- or
this pathway [43, 44]. Cancer research has also been a focus of anti-cancer effects [48]. IL-6 is essential for immunological re-
PI3K/Akt/mTOR studies. Almost all human tumors, including sponse, bone homeostasis, inflammation, and hematopoiesis when
breast cancer, have changed to this system; in fact, up to 60% of homeostatic conditions are met; dysregulation of IL-6, on the other
tumors have various variants that hyperactivate this pathway. Nu- hand, promotes the pathogenesis of numerous inflammatory and
merous cancer hallmarks, including unchecked proliferation, ge- immune-mediated disorders, including cancer. One of the signaling
nomic instability, and metabolic reprogramming in tumor cells, pathways in cancer that is most dysregulated is the IL-6 pathway. In
have been linked to the deregulation of this system. Furthermore, patients with Cancer of the ovaries, cervix, colon, stomach, esopha-
one of the primary factors contributing to cancer cell resistance to gus, head and neck, pancreas, prostate, liver, lung, and breasts, for
antitumor treatments is the activation of the PI3k/Akt/mTOR path- instance, IL-6 levels are higher in their sera [49, 50]. In breast can-
ways [45]. Thus, Understanding the PI3K/Akt/mTOR pathway is cer, IL-6 expression is associated with poor patient survival, pro-
essential for comprehending the onset and course of the disease, its motes tumor growth and invasion, and facilitates metastatic pro-
potential as a therapeutic target, and its diagnostic and prognostic gression, making the IL-6 signaling pathway a potential therapeutic

Fig. (2). An overview of the cell signaling pathways mediated by the estrogen receptors (ERs) and tyrosine kinase receptors (RTKs), Her2/Neu, two essential
building blocks in the development of breast cancer. By starting the PI3K/Akt/mTOR and MAPK pathways, their activation ultimately promotes Cancer's
hallmarks, such as cell growth, proliferation, and survival [47]. Even though PI3K/Akt/mTOR signaling is being reviewed here, it's important to remember that
several pathways are connected at different places. Two instances are shown in Figures 1-2: In addition to stimulating PI3k activation, Ras interacts with the
MAPK pathways by activating some AGC kinases (such as SGK-3) through mTOR. The picture shows that GSK-3 is also essential for controlling these path-
ways. GSK-3 inhibits and activates several molecules involved in the PI3k and MAPK pathways, demonstrating the complexity of such interactions. (A higher
resolution / colour version of this figure is available in the electronic copy of the article).
Recent Prospectives of Cellular Signaling Role for Mammary Gland Anti-Cancer Agents in Medicinal Chemistry, XXXX, Vol. XX, No. XX 5

target. Consequently, numerous therapies targeting the IL-6 path- these signal transduction pathways [60, 61]. Human tissues contain
way have been developed and assessed for breast cancer treatment. three main MAP kinase pathways; however, the one that involves
This summary reviews the biology of the IL-6 signaling pathway, ERK-1 and -2 is more pertinent to breast cancer. The main regula-
its role in breast cancer metastasis, and recent advancements in tors of ERK-1 and -2 are peptide growth factors that function
targeting the IL-6/JAK/STAT3 signaling axis. The IL-6/IL- through receptors that contain tyrosin kinase. Estradiol promotes
6Ra/gp130 receptor complex activates several signaling cascades, cell division either by raising the production of growth factors,
including mitogen-activated protein kinase (MAPK), signal trans- which in turn activates MAP kinase or by activating MAP kinase
ducer and activator of transcription (STATs), Janus kinase (JAKs), through quick, non-transcriptional effects. By both of these path-
and phosphatidylinositide-3 kinase (PI3K). Phosphorylated gp130, ways, progesterone and androgens also activate MAP kinase [59,
in turn, provides a docking site for the transcription factors STAT1 62].
and STAT3 [51-53]. Interestingly, IL-6 stimulated STAT3 to trans-
Treatment approaches for hormone-dependent breast cancer
locate into the nucleus, facilitating transcriptional activation. Tyro-
seem to cause MAP kinase activation to be upregulated. The
sine phosphatases, inhibitors of activated STATs (PIAS) that are
ERK/MAPK signalling pathways regulate cellular biological activi-
direct protein inhibitors of cytokine signaling (SOS), inhibitors of
ties like cell division, proliferation, apoptosis, and tissue formation.
activated STATs (PIAS) that are direct protein inhibitors of cyto-
They are also linked to the growth of tumours. Many human tu-
kine signaling (SOS), and JAKs and or cytokine receptors disrup-
mours, including lung, colon, ovarian, and breast cancers, have
tion are the factors that adversely control STAT3. Since transduc-
been shown to express more ERK [63]. Dndkert et al. reported that
tion, receptor availability may also constitute a limiting factor for
benign cystadenomas and normal ovarian surface epithelium exhibit
IL-6 signaling. Interestingly, transmembrane gp130 expression is
higher levels of MAPK phosphates-1 (MKP) than invasive carci-
expressed in most cells [54, 55]. However, only a limited subset of
nomas; in patients with stage III/IV cancer, MKP-1 expression was
cells may express membrane-bound IL-6Ra, which limits tradition-
significantly lower in tumour tissue than in patients with stage I/II
al signaling. It soon became clear that IL-6 signals through mecha-
disease. The phosphorylated form of ERK1/2 was much more ex-
nisms other than membrane-bound receptors, a process known as
pressed in borderline tumours, starting tumours, and normal ovarian
trans-signaling, as it modifies pleiotropic effects beyond immune
tissue. Stage III/IV patients had significantly higher P ERK1/2 ex-
cells.
pression levels in comparison to patients in stages I and II. The
Translocates into the nucleus after homodimerization to activate same ovarian cancer tissue subjected to immunohistochemistry and
transcription. Trans-signaling occurs when IL-6Ea is presented in a western blotting showed a substantial negative correlation between
soluble form by mRNA alternative splicing or proteolysis by p-ERK1 ½ and MKP-1 expression. Aberrant expression of MKP-1
ADAM10/17 [34]. Through membrane-bound gp130, IL-6 binds and ERKs may play a role in the development of ovarian cancer
sIL-6Ra, and Sgp130 represses IL-6 signaling. "Cluster signaling," [64]. Consequently, the onset and progression of the tumor may be
or "transformation," happens between two distinct cells. Introduc- closely associated with increased activation of the ERK/MAPK
ing downstream STAT3 signaling, a receiving cell's gp130 receptor signaling pathway. The immune system eliminates most tumor cells
complex reacts to a transmitting cell's IL-6/IL-6Ra complex. It was after they enter the circulatory system after infiltrating and growing
debatable for a while whether Il-6 promotes or hinders the growth in the surrounding stroma [65]. A tiny percentage of tumor cells
of breast cancer cells in vitro [56]. Recombinants IL-6 were shown with a high chance of survival make it to the intended organ, where
in early experiments to either suppress or have no discernible effect they multiply unabated, giving rise to new metastases that resemble
on the growth of breast cancer cells. In recent times, there has been the original tumor. Several signaling must be coordinated for this
a widespread recognition that IL-6 plays a carcinogenic role in process, and the ERK/MAPK signaling pathways are crucial for
certain malignancies, such as breast cancer, mostly by activating tumor invasion and metastasis. When it comes to breast cancer,
STAT3. The prior inconsistent findings may have been explained p38MAPK is also very significant. It functions as a critical kinase
by the lack of receptor expression in the tested breast cancer cell in a common pathway that influences the expression activity of the
lines or by the possibility that the activation of the JAK/STATS3 enzymes involved in the extracellular matrix degradation, which is
pathway is necessary for the pleiotropic effects of IL-6 [57]. This is essential for breast cancer invasion and metastasis [66]. Recently,
because both gp130 and IL-6Ra are necessary for signal transmis- the MMTV-PyMT mouse model of breast cancer to indicate a p38
sion. For instance, independent of STATS3, gp130 inhibits the MAPK chemical inhibitor coordination with cisplatin to reduce
advancement of the cell cycle by upregulating the G1 cycling/ p21, breast tumor size was employed. Furthermore, it has been demon-
an inhibitor of the cyclin-dependent kinase (CDK). On the other strated that melatonin inhibits the p38 pathway, which leads to
hand, gp130-induced STST3 signaling plays a contradictory role in breast cancer cell invasion. Additionally, Franyn Meng et al. fo-
regulating the cell cycle transition from the G1 to the S phase [4, cused on the physiologic role of p38y MAPK in breast cancer. It
58]. It does this through downregulating CDK inhibitors, p21, and was determined by gene expression that overexpressed p38uMAPK
upregulating cyclins D2, D3, A, and cell division cycle 25 A and resulted in significant cell cycle arrest during the G2/M phase. Fur-
p27. STAT3 upregulates target genes Bcl-2, Bcl-xl, c-mcl-1, and thermore, they claimed that rather than promoting the advancement
cyclin D1, which contribute to the growth and inhibition of apopto- of cancer, p38y MAPK's role in breast cancer was to preserve its
sis of breast tumor cells. In order to induce an EMT phenotype, oncogenic characteristics [67].
STAT3 additionally upregulates the expression of Twist, Snail,
MMP2, MMP9, and vimentin. In support of this observation, 2.9. Antiapoptotic Protein Role in Breast Cancer
STATS3 knockdown was found to reduce the establishment of the
atmosphere, the CD44+ subpopulation, and the expression of the Programmed cell death was originally described as a cell self-
stemness genes oct-4 and Sox-2 in the proteins of breast cancer destruction process that plays a crucial role during the development
cells [59]. of metazoans. The term apoptosis was invented to describe a type
of programmed cell death that has specific microscopic features
2.8. ERK/Mitogen Activation Protein Kinase (MAPK) Signaling such as chromatin condensation, nuclear fragmentation and plasma
in Breast Cancer membrane blebbing. For a long time, the terms apoptosis and pro-
grammed cell death were used synonymously until autophagic cell
Signals for cell growth and death are transmitted and amplified death and programmed necrosis were brought to the attention of the
by mitogen-activated protein kinase (MAP kinase) cascades. The research community [55]. Autophagic cell death was initially char-
degree of trafficking caused by different growth factors, steroid acterized by microscopic features of dying/dead cells. Autophagic
hormones, and G protein receptor-mediated ligands is indicated by cells often lack the typical features of apoptotic cells and almost
6 Anti-Cancer Agents in Medicinal Chemistry, XXXX, Vol. XX, No. XX Kashyap et al.

always contain multi-layer or double -layer intracellular membrane patient-derived ER+ breast cancer xenografts show increased tumor
structures enclosing a bulk of cytoplasmic material or subcellular cell death and decreased tumor growth. Comparable outcomes were
organelles. These structures, termed autophagosomes, are also ob- observed when combining the Bcl-2 selective inhibitor ABT-199
served in yeast cells upon nutrient starvation. Autophagosomes fuse with Tamoxifen, but in this setting, BH3-mimetics alone could not
with lysosomes to form autolysosomes and the contents of autoly- stop tumor growth or trigger apoptosis [2]. ABT-737 enhanced
sosomes are digested by lysosomal proteases. Autophagy-related Irradiated TNBC cell death in cell culture and vibrant sensitized
genes (ATGs) are involved in various stages of autophagy, includ- patients-generated xenografts of basal-like breast cancer to the
ing initiation, nucleation, maturation of autophagic vesicles, and chemotherapy medication docetaxel in TNBC models. In HER2+
fusion of autophagic vesicles with lysosomes. These proteins can be breast cancer cells receiving radiation therapy, GX15-
viewed as the core players of autophagy. Notably, several of these 707(obatoclax), a pan Bcl-2 family inhibitor, works in tandem with
autophagy core players have been implicated in apoptosis [62]. On the EGFR/HER2 inhibitors lapatinib, an EGFR/HER2 inhibitor, to
the other hand, after infants are weaned, cell death overproliferates cause cell death. According to this research, targeting Bcl-2 family
to eliminate milk-producing MECs, and lobular involution during proteins in conjunction with the targeted therapies and current
menopause is encouraged by The Bcl-2 protein family. It is part of chemotherapies may enhance the death of tumor cells and, as a
the intrinsic apoptotic pathway, which controls the cellular com- result, improve the prognosis for breast cancer patients. While
mitment to apoptosis in the breast and many other tissues [71]. antiapoptotic Bcl-2 family member inhibition in breast malignan-
There are two primary subclasses of Bcl-2 proteins: pro-apoptotic cies is not currently being studied in clinical trials, preliminary
(Bad, Bak, Bax, Bid, Bim, Bik, Hrk, Noxa, and Puma) and Bcl2- phase I studies in small-cell lung cancer indicate that ABT-263 is
A1, Bcl-2, Bcl-xl, Bcl-w, and Mcl are antiapoptotic. Family: Pro- safe and well tolerated in individuals with solid tumors. Further-
and antiapoptotic members interact intricately to integrate signaling more, phase trials are being conducted to evaluate the effectiveness
data and control cell death decisions [72]. Because the breast is a of ABT-263 in conjunction with gemcitabine, paclitaxel, and soraf-
dynamic organ with periodic cycles of protein dysregulation, it can enib for solid tumors, potentially encompassing beast malignancies
obstruct development at various pivotal points. [8].
Moreover, persistent deregulation of the Bcl-2 family is linked
2.10. Androgen Activation Role in Breast Cancer
to cancer's hallmark of evading cell death. Bcl-2 dysregulation in
the setting of breast tumors encourages innate or acquired treatment The AR has a well-established congenital role in prostate can-
resistance. The involvement of members of the Bcl-2 family in cer and has been extensively researched in male physiology. Since
breast development, carcinogenesis, and treatment resistance will the mid-1970s, several organizations have provided light on the
be the main topics of this review [73]. One member of the family, involvement of AR in breast cancer as a receptor of precursor lig-
Mcl-1, will be highlighted as a possible target for therapy in breast and of the estrogen receptor (ER) [78]. Indeed, this multifunctional
cancers. role could be partially explained by the multiple pathways to which
The release of cytochrome-c into the cytoplasm results from AR has been linked. It could also be presented from a metabolic
mitochondria outer member permeabilization (MOMP), a character- perspective, given that androgen is located between pathways that
istic of the intrinsic apoptotic pathways (IAP). Pro-and antiapoptot- can have conflicting effects on progestin and estrogen synthesis.
ic Bcl-2 proteins interact hierarchically to control this apoptotic The structure of androgen receptors and the length of the AR pro-
pathway. Among the four highly conserved Bcl-2 homology (BH) tein are estimated to be 918 amino acids. It is a member of the large
domains, at least one from Caenorhabditis elegants to humans is family of hormone-regulated transcription factors known as the
present in every member of the Bcl-2 family. The Bcl-2 family's steroid nuclear superfamily [79]. These transcription factors have a
protein interactions, which are essential for controlling MOMP, are modular tripartite structure comprising two domains, an amino
facilitated and stabilized by BH3 domains. While the exact mecha- terminus (Nt) and a carboxy terminus (Ct), divided by a central
nism underlying MOMP remains unclear, the majority of suggested domain. AR is encoded by a single copy gene almost 90 kb long
explanations imply that the Bak and Bax, two effectors of the Bcl-2 and found on the X chromosome in the all-ql2 region. Its transcript
family, heterodimerize to produce higher-order oligomers, which in yields an mRNA with an open reading frame (ORF) of roughly 2.8
turn open cytochrome-escaping holes in the outer mitochondrial kb and has eight exons. When codes for two proteins, one with an
membrane (OMM) that let it enter the cytoplasm. As a result, apparent molecular weight of 87 kDa (the-N-truncated from, where
Bak/Bax activity is tightly controlled on several levels. Subcellular translation begins at the internal methionine 188) and the other with
localization is one regulatory level influencing the Bak/Bax interac- a molecular weight of 110 kDa full-length. The two proteins differ
tion [74]. Bak maintains the intrinsic apoptotic pathway's baseline at the Nt [80]. The AR protein contains five functional domains:
activity and is linked to the OMM. In the meantime, Bax responds two activation functions, AF-1 and AF-2 (also called transcription-
to apoptotic cues by moving from the cytoplasm to the mitochon- activating functions, or TAF); AF-1 is the principal transactivation
dria, indicating that Bax location modifies the cells' susceptibility to domain and is found in the Nt, while AF-2 is highly conserved
apoptotic stimuli. A Bak/Bax- Bax-expressing cell at a high level at across species and is found In the CT; The ligand-binding domain
the OMM is more likely to die via the intrinsic apoptotic pathway. (LBD), which is in charge of binding agonist and antagonist mole-
Furthermore, Bak and Bax include BH1-3 domains necessary for cules; the nuclear localization function required for the transloca-
their interaction. But before Bak/Bax experiences a significant con- tion of AR into the cell nucleus; the hinge domain (HD), which is
formational shift brought on by the binding of pro-apoptotic Bcl-2 situated between the DBD and LBD and allow for flexibility as a
activators (Bim, Puma, and Noxa), they cannot interact. Activators binding site for regulatory proteins. The last domain is DNA bind-
are called "BH3-only" proteins because they solely include BH3 ing (DBD), which is required for binding to the androgen-
domains [75]. responsive elements in the regulatory regions of target genes [81].

Preclinical models support the use of BH3-mimetics in conjunc- 3. HORMONAL AND NON-HORMONAL MECHANISMS
tion with existing breast cancer therapies—therapy techniques, UNDERLYING BREAST CANCER:
despite the lack of information addressing their usage in clinical
breast malignancies. For instance, Bcl-2 is overexpressed in around Numerous research groups have focused on AR since it is ex-
85% of ER+ breast tumors, possibly due to ERalpha directly binding pressed in 60-70% of breast malignancies and may collaborate with
and transactivating its promoter. An analog of ABT-263, ABT-73 ER in ER-negative and ER-positive tumors [82]. According to ex-
inhibits Bcl-2/Bcl-xl/Bcl-w, and when combined with Tamoxifen, pression microarray research, ER/AR+breast tumors have been
used in AR-targeted therapies because they display intact and active
Recent Prospectives of Cellular Signaling Role for Mammary Gland Anti-Cancer Agents in Medicinal Chemistry, XXXX, Vol. XX, No. XX 7

AR signaling, previously recognized as breast tumors with histolog- kinase inhibitors targeting EGFR and HER2 may be effective
ically apocrine features [82, 83]. against cancers that are resistant to these inhibitors and those that
have never been treated with one. These findings have led to the
3.1. Tamoxifen continuation of a phase III trial using letrozole plus the dual inhibi-
tor GW572016 in women with ER-positive metastatic breast can-
In many different contexts, Tamoxifen is recommended for the cer, as well as many phase II trials combining gefitinib
treatment of breast cancer. It should be mentioned that data indi- with hormonal treatment [89].
cates that Tamoxifen may be more beneficial for people whose
tumors are favorable for the estrogen receptor [84]. The drug was 3.2.2. Trastuzumab
first created in 1962 for use as a birth control pill, but that plan was
abandoned. Instead, it proved to be a highly effective anticancer For women with HER2-positive breast cancer, trastuzumab, a
treatment. In several bodily regions, Tamoxifen demonstrates estro- monoclonal antibody targeting HER2, is effective when used alone
genic agonist and antagonistic effects. It is a patient-specific selec- or in conjunction with chemotherapy. Combining trastuzumab with
tive estrogen receptor modulator (SERM) due to its dual activity of chemotherapy results in better overall survival rates, longer times
preferentially binding to estrogen receptors and exerting estrogenic for disease progression, and higher response rates than chemothera-
and anti-estrogen impact [85]. It produces antiestrogenic and anti- py alone. There appears to be little question that signaling through
cancer actions in breast tissue by antagonistically competing with HER2 is crucial for the development, growth, and survival of breast
estrogen for binding sites. It is categorized as cytostatic because it cancer [90]—combining trastuzumab with chemotherapy results in
slows the cell cycle through subsequent intracellular mechanisms. It better overall survival rates, longer times for disease progression,
has an estrogenic agonist effect in bone, stimulating estrogen recep- and higher response rates than chemotherapy alone. Undoubtedly,
tors rather than inhibiting them, possibly shielding postmenopausal HER2 signaling is essential for breast tumor growth, progression,
women from osteoporosis. and survival. Less is known about HER3 and HER4 functions in
breast cancer. In 15-35% of initial breast cancers, HER3 is overex-
In premenopausal women, it also functions as an estrogen ago- pressed; this overexpression may be linked to worse local control
nist in the hypothalamus, raising gonadotropin levels and perhaps and overall survival. Despite lacking clinical evidence, it aligns
triggering ovulation. Triple-negative breast cancer is known to with HER3's established function as EGFR (ErbB1) and HER2
overexpress NOTCH1 and NOTCH4 receptors, and increased ex- essential partner for signaling via the PI3K pathway.
pression of the Notch ligand JAGGED1 is associated with a poor
prognosis in breast cancer. 4,5 Tamoxifen's pharmacological inter- On the other hand, it seems that in vitro human breast cancer
ference with estrogen receptor (ER) activity results in increased cells require and respond to HER4 activation for antiproliferative
Notch signaling, which could be an unintended consequence of and differentiation responses [91]. This could be attributed to
Tamoxifen's present use in breast cancer treatment. Research on HER4's diminished ability to stimulate proliferation through the
Non-canonical Notch signaling, regulated by p53 and IKK al- Ras/Raf/mitogen-activated protein kinase signal transduction path-
pha/IKK beta, activates IL-6/JAK/STAT signaling in breast tumor ways. In some patient populations, trastuzumab may cause TKIs to
cells. using MCF 7(p53 and IKK alpha/IKK beta) and MDA-MB- be highly active. Predicting sensitively to TKIs, however, is unlike-
231 (IL-6/JAK/STAT) cell lines, researchers find potential inhibitor ly to be as simple as it was for trastuzumab; the evidence to date
activities on p53 and IKK alpha/IKK beta and IL-6/JAK/STAT indicates that receptor overexpression alone is insufficient to pre-
signaling.] It has been suggested that there are several ways in dict response [92].
which the ER and ErbB pathways interact, such as tamoxifen stimu- 3.2.3. Ruxolitinib
lation of EGFR and HER2 expression, ER ligand-independent sig-
naling through PI3K, and the modification of ER coactivators by Ruxolitinib is a powerful and specific inhibitor of JAK1 and
downstream ErbB pathway effectors [86]. In preclinical models, JAK2. Patients with polycythemia vera who have not responded
HER2-overexpressing breast cancers with co-blockade of the EGFR well to hydroxyurea or are intolerant of it and those with intermedi-
and ER pathways with gefitinib and either tamoxifen or fulvestrant ate or high-risk myelofibrosis are approved to receive it. Rux-
restored tamoxifen sensitivity and delayed the development of re- olitinib is a solid and selective inhibitor of JAK1 and JAK2, with
sistance to estrogen deprivation. IC50 values less than 5Nm in enzyme tests. It exhibits moderate to
significant selectively against JAK3 (IC50 ¼ 428 +- 243Nm) and
3.2. Epidermal Growth Factor Receptor Inhibitors (EGFR) TYK2 (IC501/4 19+-3.2 Nm), in that order [93]. Ruxolitinib ob-
structs several cytokines and growth factors critical for the immune
3.2.1. Gefitinib and Erlotinib system and hematopoiesis signaling. Ruxolitinib, also known as
In vitro and xenograft models, gefitinib and erlotinib exhibit jakavi or jakafi, is presently approved for the treatment of patients
efficacy against several breast cancer cell lines. The most often with intermediate-or high-risk myelofibrosis, which includes prima-
reported side effects in clinical studies were vomiting, asthenia, ry myelofibrosis, post-polio myelofibrosis, and post-essential
diarrhea, grade 1 or 2 rashes, and nausea. Nevertheless, when it thrombocythemia vera myelofibrosis. It is also approved for the
comes to treating resistant metastatic breast cancer, neither gefitinib treatment of polycythemia vera patients who are intolerant of hy-
nor erlotinib have shown any appreciable single-agent activity. Out droxyurea or who have not responded well to it [94].
of 113 patients, only three had partial responses, and eight had sta-
ble illness for six months or more across three phase II studies with 4. NEW PROTEIN KINASE INHIBITORS IN BREAST
gefitinib [87]. Phase I trials are underway for EKB-569, an irre- CANCER: AFATINIB AND NERATINIB
versible EGFR inhibitor, to treat advanced solid cancers. As of right 4.1. Afatinib
now, response data for breast cancer have not been released. It ap-
pears doubtful that monotherapy with EKB-569 will have a signifi- Human epidermal growth factor receptor 2 (HER2) is overex-
cant level of activity in an unselected and extensively pretreated pressed in 20-25% of breast cancers and has previously been a poor
group of women with advanced breast cancer, given the experience prognostic indicator.
with gefitinib and erlotinib [88]. ErbB receptor promiscuous heter- The treatment of metastatic breast tumors has significantly
odimerization enables signaling via a range of receptor-receptor shifted since the first completely humanized monoclonal antibody
pairings. Thus, overexpression of other receptor family members targeting HER2, trastuzumab, was introduced. Nevertheless, most
could be a potential route of resistance to drugs targeting a single patients experience resistance despite their early response. Accord-
ErbB receptor, such as trastuzumab or gefitinib. As a result, dual
8 Anti-Cancer Agents in Medicinal Chemistry, XXXX, Vol. XX, No. XX Kashyap et al.

ing to recent evidence, methods that target multiple members of the tion. The three most prevalent solid tumor types were head and
HER family may provide synergistic effects and circumvent neck (14%), colorectal (26.1%), and breast (26.9%) [104]. The
trastuzumab resistance [95]. Preclinical tumor models that include safety profile of up to 400 mg and 150 mg twice daily was favora-
trastuzumab-resistant cell lines (SUM 190-PT) overexpressing ble. PFS was 5.5 months on average for patients with HR/HER2
EGFR and HER2, as well as HER2-negative cell line (SUM 149- negative breast cancer. Hyperglycemia (52%), nausea (51%), de-
PT), and many in vivo models have all shown preclinical activity in creased appetite (42%), diarrhea (40%), and vomiting (31%) were
response to afatinib. Specifically, afatinib demonstrated efficacy in the most frequent adverse events. Nine patients had dose-limiting
mice xenografts overexpressing EGFR/HER1/and HER2, causing toxicities (DLTs) during the dose-escalation phase [105]. Among
partial and total tumor reduction [96, 97]. the DLTs were combination hyperglycemia and hypophosphatemia
(n=1 at 150 mg twice daily dose), nausea (n=2 at 450 mg once daily
4.2. Neratinib dose), and hyperglycemia (n=2 at 450 mg once daily dose and n=4
at 200mg twice daily dose). One of the most critical mechanisms
The effectiveness of neratinib in conjunction with capecitabine controlling cell growth, survival, and proliferation is the
was investigated in 621 patients with metastatic HER2-positive PI3K/AKT/mTOR pathway [106]. Targeting these three crucial
breast cancer who had previously undergone two or more anti- locations in this system has led to the development of treatment
HER2-based treatments in NALA(NCT01808573), a randomized, methods for breast cancer. In HR+/HER2 negative MBC,
multicenter, open-label clinical trial [98]. Lapatinib 1250 mg orally BOLERO-2 was a randomized, double-masked, phase III placebo-
once daily on days 1-21 with capecitabine 1000mg/m2 given orally controlled trial that assessed the effects of exemestane and placebo
twice daily on days 1-14 for each 21-day cycle (n=314) or neratinib versus the mTOR inhibitor everolimus in combination with it. Dou-
240 mg orally once daily on days 1-21 with capecitabine 750 ble PI3KCA mutations are frequently detected in breast tumors that
mg/m2 given orally twice daily on days 1-14 for each 21- day cycle are HR+/HER2 negative [106].
(n=307) were the two groups of patient who were randomly as-
signed (1:1). Patients received treatment until the condition wors- 5. ISOFORM-SPECIFIC PI3K INHIBITORS
ened or the toxicity became intolerable [99].
Compared to pan-PI3K inhibitors, isoform-specific PI3K in-
4.3. Doxorubicin hibitors may provide the possibility of higher doses and greater
efficacy with less harm.11 The phase III SANDPIPER clinical trial
One anthracycline antibiotic used as an anticancer agent is dox- examined the beta-sparing PI3K inhibitor temalisib [107]. In the
orubicin. Due to its cardiotoxicity, long-term treatment of this anti- trial, 516 postmenopausal women were randomly assigned to re-
cancer medication may result in the accumulation of its metabolite, ceive fulvestrant+ placebo or fulvestrant plus taselisib. PFS was
doxorubicinol, which can lead to cardiomyopathy [100]. The body evaluated by the investigators and improved in the combination
accumulation of doxorubicin and doxorubicin determines the cardi- treatment group from 5.4 months to 7.4 months (HR 0.70, P=0037).
otoxic impact. This study aimed to examine the amounts of doxoru- The most frequent grade ¾ adverse events (AEs) were colitis, sto-
bicin and doxorubicin in breast cancer patient's blood plasma. To matitis, diarrhea, and hyperglycemia [108].
investigate individualized therapy options with molecularly targeted
medicines, a number of receptors are extensively tested for BC 5.1. Docetaxel
patients, including progesterone, estrogen and human epidermal
growth factors. For instance, doxorubicin and docetaxel together exhibit signif-
icant efficacy. The combination of docetaxel 75mg/m2 and doxoru-
Nevertheless, conventional treatment methods such as surgery,
bicin 50mg/m2 showed much more activity than doxorubicin plus
radiation, and chemotherapy are preferred for patients who are tri-
cyclophosphamide (AC). In one randomized trial, resulting in a
ple negative (ER-, PR-, and HER2-), those who have intrinsic or
longer time to progression and a higher response rate (60% vs.
acquired resistance to targeted therapies, and patients whose ill-
47%) [109]. A second study involved the randomization of 484
nesses have spread. The research ethics committee of the "Dhar-
individuals receiving 5-fluorouracil plus doxorubicin and cyclo-
mais" cancer hospital approved this study. Thirty patients with
phosphamide or docetaxel plus doxorubicin and cyclophosphamide
breast cancer who were on DOX medication participated in this
(TAC). Patients with poor prognostic characteristics were included
trial. The participants completed informed consent forms before
in the TAC arm, where the response rate was much higher (54% vs.
sampling and received a detailed explanation of the process [101,
42%). Patients receiving TAC experienced febrile neutropenia more
102]. Adriamycin-cyclophosphamide (AC) and 5-fluorouracil-
frequently, although the risk of infection and septic mortality was
cyclophosphamide (FAC) were the two treatment regimens for
minimal and not higher than in the 5-
breast cancer. The dosage ranges for the FAC and AC regimens
fluorouracil/doxorubicin/cyclopamine group. Research on docetaxel
were 68-90 mg and 81-100 mg, respectively. The patients received
as a neoadjuvant is currently ongoing [110]. Three randomized
chemotherapy in cycles 1,2,3,4,5and 6. Every cycle lasted three
trials' findings show that when neoadjuvant docetaxel is used se-
weeks. 2020 saw a rise in female breast cancer diagnoses over Can-
quentially, locally advanced breast cancer patients experience better
cer, making it the most frequent cancer worldwide and the primary
clinical and pathological outcomes. Trastuzumab, a platinum salt,
cause of death for women. For the previous three years, there have
and docetaxel are being studied in conjunction with individuals
been more than two million new cases and more than 600,000 fatal-
with HER2-positive breast cancer. Two phase II trials that assessed
ities annually. A search in the Scopus database for" breast cancer"
the combination were recently completed by the Breast Cancer
yields 558,676 results. There are more and more publications on
International Research Group (BCIRG) [111].
this topic yearly; in the last year alone, 33,597 documents were
published. The problem of breast cancer remains unsolved, even
5.2. Letrozole
with the scientific community's intense interest and the develop-
ment of novel therapeutic approaches [103]. Letrozole is a nonsteroidal aromatase inhibitor that effectively
inhibits estrogen production. In postmenopausal breast cancer pa-
4.4. Alpelisib tients, letrozole significantly reduced the plasma levels of estrone,
estradiol, and estrone sulfate. In ovariectomized animal models of
In PIK3CA, they changed advanced solid tumors; the first
postmenopausal estrogen-dependent breast cancer, letrozole
phase of a human study was conducted to demonstrate the effec-
demonstrated antitumor effects. Moreover, letrozole was found to
tiveness and tolerability of alpelisib. Eighteen 134 patients with
be more effective than tamoxifen in reducing cellular proliferation
advanced, unresectable solid tumors were included in this investiga-
Recent Prospectives of Cellular Signaling Role for Mammary Gland Anti-Cancer Agents in Medicinal Chemistry, XXXX, Vol. XX, No. XX 9

markers in estrogen-dependent tumors that overexpress HER1 and possible, so they should be considered for endocrine surgery or
HER2 [112]. In postmenopausal women, both healthy and those chemotherapy [120]. The results of chemotherapy with Thiote-
with a history of breast disease, letrozole increased markers of bone paThiotepa (trimethylene thiophosphoramide) are examined here;
resorption. Letrozole has a broad volume of distribution (1.87 L/kg) out of a total of 46 individuals of this type, the concomitant use of
and is approximately 60% bound to plasma proteins. It is primarily testosterone and ThiotepaThiotepa in breast cancer patients having
eliminated through urine after being metabolized by the cytochrome obtained the remarkable objective remission rate of 85 percent. Of
P450 enzyme system, with a mean elimination half-life of 82 hours. the 34 patients they saw, seven were at stage 2. Even if these are
Letrozole competitively binds to the heme of the cytochrome P450 excluded, 23 of the remaining It was reported that 27 patients had
(CYP) subunit of the aromatase enzyme, inhibiting its activity. In metastatic illness After the first five injections of testosterone,
postmenopausal women with breast cancer, letrozole inhibited both Thiotepa (15 mg) was injected intramuscularly (Table 1) [121].
whole-body and in-situ aromatization in breast tumors. Letrozole is
a powerful inhibitor of estrogen synthesis [113]. In a crossover 6. HERBAL DRUGS USED IN BREAST CANCER
study involving 12 postmenopausal women with estrogen receptor-
positive advanced breast cancer, letrozole (2.5 mg/day) led to great- 6.1. Goldenseal (Hydrastis canadensis)
er reductions in plasma hormone levels compared to anastrozole (1 Hydrtastis canadensisL, also known as goldenseal, is a herb
mg/day): 84.3% versus 81.0% for estrone (p = 0.019), 87.8% versus utilized as a dietary supplement in many traditional medical sys-
84.9% for estradiol, and 98% versus 93.5% for estrone sulfate (p = tems. Native Americans have long used it as a coloring agent and
0.0037). Thus, letrozole significantly suppressed plasma estrogen therapeutic cure for common illnesses and disorders, such as can-
levels more than anastrozole. After oral administration, letrozole is cer, ulcers, digestive issues, and wounds; goldenseal has gained
rapidly and almost completely absorbed from the gastrointestinal popularity in the USA and other countries as a dietary supplement
tract, with an absolute bioavailability of 99.9%. The mean maxi- [143]. This plant's rhizome has been used to cure various illnesses,
mum plasma concentration (Cmax) is reached at a median of 2 such as ulcers, gastrointestinal issues, constipation, nervous prostra-
hours (mean 8 hours) after a single 2.5 mg dose [114, 115]. tion, edema, skin and eye infections, and journal per-proof two
cancers—one of the most bioactive alkaloids found in various por-
5.3. Cyclophosphamide tions. Berberine is one of the most bioactive alkaloids identified in
CD4CD2 Additionally, Foxp3 regulatory T cells (Treg) play a different parts of goldenseal. The goldenseal extract containing
significant role in preventing autoimmune disorders and encourag- berberine showed numerous therapeutic effects such as antimicro-
ing the growth of tumors. Antitumor T-cell responses that arise bial, anti-inflammatory, hypolipidemic, hypoglycemic, antioxidant,
spontaneously are common in advanced-stage tumors; at both stag- neuroprotective (anti-Alzheimer’s), cardioprotective, and gastroin-
es of native T-cell development, Treg potently suppresses them. testinal protective (Figs. 3-8) [144].
However, in cancers with more advanced stages, a bad prognosis is
linked to tumor buildup in the tumors and draining lymph nodes of 6.2. Turmeric (Curcuma longa)
many cancer types. Using constitutively expressed surface markers, Turmeric's scientific name is Curcuma longa. It imparts a deep
several therapeutic trials have attempted to deplete them. However, yellow hue to cuisine. The rhizome and turmeric's rootstock contain
the circulating Treg quickly recovered within a week or two follow- curcumin, the plant's active element. Due to its phenolic compo-
ing the depletion [116]. However, there was disagreement over nents, curcumin is recognized to have anticancer properties. Tur-
clinical responses. Recently, the lethal alkylating nitrogen com- meric inhibits the spread of stomach, skin, lung, and breast cancer.
pound cyclophosphamide (CTX). In mouse models, mustard chem- The antioxidant curcumin alters the synthesis of eicosanoids, in-
icals were found to have an impact on Treg decrease when adminis- cluding prostaglandin E- 2(PGE-2). It also possesses anti-
tered exclusively at low doses and on a metronomic regimen, and inflammatory qualities in humans [145].
twenty-one days of metronomic low-dose CTX therapy selectively
reduced CD4CD25 Foxp3 Treg in a trial including many late-stage Curcumin has been discovered to have an inhibitory effect on
cancer patients. Extended low-dose CTX therapy may prevent the initiation and spread of Cancer. Turmeric inhibits the synthesis
Treg-induced immune suppression and enhance patients with ad- of nitrosamines, which increases the body's natural antioxidant
vanced-stage cancer clinical prognosis and their spontaneous anti- capacity. Curcumin increases the amount of glutathione and other
tumour T-cell responses [117]. Flow cytometry determined the non-protein sulphahydryls, which act directly on several enzymes.
frequency of CD4CD25 Foxp3 Treg among all CD4 T cells before Curcumin contains a broad range of biological effects that include
receiving CTX therapy. When comparing patients to healthy indi- the prevention of Cancer, ischemia, inflammation, and aging [19-
viduals, there was a small but non-significant rise in Treg [118]. 21]. Thus, curcumin's possible therapeutic uses in conditions related
Fourteen days after starting CTX treatment, Treg significantly de- to metabolism, infections, atherosclerosis, autoimmune disease, and
creased until day 42 in all patients (3.0+1.8% versus neurological conditions. [11, 12, 22, 26]. Additionally, curcumin
5.1+3.0%;P=0.002). After that, Treg progressively improved till has potent antioxidant qualities. Reducing the quantity of oxidative,
day 84 of CTX treatment (5,2+2.1%) and showed signs of complete damaging, and cancer-causing DNA molecules in tissue samples
restoration. Similarly, in just 14 days, the absolute quantity of Treg can stop or reverse DNA damage [146].
decreased (19,000+8,600\ml to 11,000+1,200/ml). It steadily pro- Research examining curcumin's anticancer properties in breast
gressively grew until day 56 (22,000+7,700\ml) when pre-treatment cancer has revealed that this compound works through several dif-
levels were attained, which wasn't the case with absolute numbers ferent molecular targets. These consist of the following:
of grew further until pre-treatment values were achieved on day 56 EGRF/PEGFR signaling pathway, Akt/mTOR pathways inactiva-
(22,000 +7,700/ml), whereas the absolute amounts of drug [119]. tion, suppression of FABP5/PPAR/pathway, overexpression of
TIMP 1 and 4 expressions, apoptosis Inhibition of cell
5.4. Thiotepa growth, the onset of cell cycle arrest at the G2/M phase, and soon.
The problem of how to handle a specific instance of advanced Curcumin affects several molecular targets in the cell signal system,
carcinoma of the breast confronts each medical professional treat- including PPAR, TGF-1, ERK1/2, ERK5, EBP, NF-B, Nrf2,
ing malignant illness. The first person to treat such individuals Notch-1, AMP,-catenin, ERK1/2, ERK5, and STAT3. Nuclear fac-
should always be essential hormone therapy for a test duration to tor-B (NF-B), a pro-inflammatory transcription factor, alters the
check if this is a manner that they can be regulated, if this is either expression [147]. Similarly, Curcumin and Paclitaxel suppress the
chemotherapy or endocrine surgery [120]. The outcomes are not overexpression of Bcl, p53, Rho-A and C-Ha-Ras in basal like
10 Anti-Cancer Agents in Medicinal Chemistry, XXXX, Vol. XX, No. XX Kashyap et al.

Table 1. Various Anticancer Drugs are involved in the treatment by different cellular signaling Targets [122-181].

S. No. Drug Name Target Phase of Development Clinical Outcomes References

Highly effective antibiotic-based chemotherapeutic. Major

Anthracycline inhibits DNA
1 Doxorubicin Approved adverse side effect is cardiotoxicity. Liposomal formulation [94, 109]
synthesis
available for clinical use.

Alkylating agents inhibit DNA Significantly increases survival rate when used in combina-
2 Cyclophosphamide Approved [122]
synthesis tion with Anthracycline or Taxanes

Standard treatment for estrogen receptor positive breast

Selective estrogen receptor
3 Tamoxifen Approved cancer for premenopausal women significantly increase [123]
modulator
survival increased risk of endometrial cancer

Reversibly binds to microtubu- The predominant toxicity was grade 3-4

4 Doxicetaxel lin with high affinity in a 1:1 G2\Mphase neutropenia, occuring in 92% of the patitents, [102]
stoichio-metric ratio. although febrile neutropenia arose in 10% of the patient

With anthracycline as a monotherapy affective in combina-

5 Pacetaxel Taxane, mitotic inhibitor Approved [124]
tion with anthracyclines
Alkylating agent, inhibits DNA Affective after treatment with anthracycline and taxane
6 Vinflunine Phase 2 [125]
synthesis major side effect is Leukopenia
Alkylating agents inhibit DNA Significant tumour control rate after pre-treatment metastatic
7 Capecitabine Approved [126]
synthesis breast cancer patient increase risk of cardio toxicity
During RNA and DNA synthe- After 6 months, there was no significant clinical difference
8 Methotrexate sis is cytotoxic during the S- S phase observed between the patients receiving the anti-TNF thera- [127]
phase of the cell cycle py
Binding to the aromatase
enzyme,and through competi-
tive inhibition blocks the The development of histologically confirmed breast cancer
9 Anastrazole phase 2 [128]
conversion of androgen to either invasive or non invasive (ductal carcinoma insitu)
estrogen in peripheral (ex-
tragonadal) tissues.
Inhibits phosphorylation ErbB
family as well as downstream Substantial clinical activity both heavily pretreated and
10 Neratinib phase 1 [129]
pathways including ERK and trastuzumab naïve patients.
AKT
On target BTK inhibitor
off target kinase inhibitor and Inhibited proliferation of cancer cells invitro and ibrutinib
12 Ibrutinib immunomodulation phase 2 treated mice display significantly lower tumour burdens and
metastasis compared to control
By interference with suppres-
[130]
sor cell
DMF covalently modifies the
NFkB transcription nuclear
Inhibits the nuclear factor kBpathways in breast cancer cells
13 dimethyl fumarate translocation and nuclear phase 3 [131]
by covalent modification of p65 protien
translocation and DNA binding
activity
Estrogen receptor monomers
inhibits receptor dimerization,
14 fulvestrant phase 2 Median progression free survival (PFS) of 16.6 months [132]
activating function 1(AF1) and
AF2 are rendered inactive

It functions as an agonist with

Induction of secretory changes in the endometrium, increase
a higher affinity to the proges-
15 megestrol phase 2 in basal body temperature, pituitary inhibition and produc- [111]
terone receptor than progester-
tion of withdrawal bleeding in the presence of estrogen.
one

(Table 1) Contd….
Recent Prospectives of Cellular Signaling Role for Mammary Gland Anti-Cancer Agents in Medicinal Chemistry, XXXX, Vol. XX, No. XX 11

S. No. Drug Name Target Phase of Development Clinical Outcomes References

Selectivity inhibit PIK3 in the PI3K/AKT Overall response rate was 12.5%, with
16 Alpelisib Phase 1 [104]
kinase signaling pathway partial responses

Adsorb to calcium phosphate crystal in High blood calcium level and certain
17 Aredia bone may directly block disolution of this Phase 3 bones probl thar may occur some type of [133]
mineral compound of bone cancer

Raloxifene hydro- Venous thromboembolism precipitate in

18 Binding to estrogen receptor Phase 2 [134]
chloride about 1 out of 100 patients

May stop the growth of tumor cell by

Blocks growth-driven transduction signal in
19 Everolimus Phase 2 blocking some of the enzymes needed for [135]
a T cell response to allo antigen
cell growth

Makes iron available for critical cellular Selective estrogen receptor modulators are
20 Fareston processes while protecting lipid DNA and - therapeutically equivalent to treatment for [136]
protein from potentially toxic effect of iron metastasis

Act as a potent inhibitor of pituitary gonad- Block the androgen receptor on tumor
21 Goserelin otropin secretion when administrated in the - cells and may cause them to stop growing [137]
biodegradable formulation or die

Vary favorable treatment outcomes and

Act as potent inhibitor of pituitary gonado-
good tolerability among Koreans post-
22 Letrozole tropin secretion when administrated in the - menopausal women with ER positive
[138]
biodegradable formulation
breast cancer

Inhibit cell growth and suppresses DNA

To treat HER2 negative and HR positive
23 Palbociclib replication in retinoblastoma tumor sup- - advanced or metastatic breast cancer
[139]
pressor gene (RB) proficient cancer cell

61% of patients taking Lynparaza were

Targets PARP to disrupt the DNA repair
24 Lynparza Phase 3 alive and did not see their cancer grow or [99]
process and potentially kill tumor cell
return at a median follow up of 3.4 year

Inhibit poly (ADP-ribose) polymerase , Median overall survival from olaparib

25 Olaparib thereby blocking the repair of single -strand - initiation was 1002 days (95% Cl:676; not [91]
DNA breaks calculable)

Bind directly to beta-tubulin subunits or

26 Lxempra microtubules leading to suppression of Phase 3 20 patients achieve stable disease [116]
microtubule dynamic

Binds to specific protien called FKBP -12

and forms a complex which inhibits the
People with kidney cancer who took
27 Afinitor activity of mTOR, reducing cell prolifera- - Afinitor had a response rate of 2%
[140]
tion the formation of new blood vessels,in
glucose uptake

Damage DNA directly at every phase of the Treat a certain type of cronic lymphocytic
28 Chlorambucil Phase 2 [181]
cell cycle leukemia

Incidence of severe viral and bacterial

Form DNA crosslink that leads to a reactive infections was reduced and immunosup-
29 Thiotepa Phase 2 [121]
metabolite pressant could be discontinued in 77% of
patients at 1 year

(Table 1) Contd….
12 Anti-Cancer Agents in Medicinal Chemistry, XXXX, Vol. XX, No. XX Kashyap et al.

S. No. Drug Name Target Phase of Development Clinical Outcomes References

Inhibit the tyrosine kinase activity asso- Clinical benefit rate was 57.5% in cohort one
30 Lapatinib Phase 1 [141]
ciated with two oncogenes EGFR HER2 and 40% in cohort 2

Demonstrated its efficacy in treating

31 Margetuximab Target the HER2 oncoprotein Phase 3 [142]
HER2+MBC

CDK 4/6 inhibitors, developed to inhibit

cell-cycle progression, hormone
CDK4/6 inhibition in hormone receptor-
32 Abemaciclib receptor-positive and human epidermal Approved [181]
positive/HER2-negative breast cancer
growth factor receptor 2 (HER2)-
negative metastatic
Human epidermal growth factor receptor
Ado-Trastuzumab Research consortium trial HER2-positive advanced BC and discuss our
33 2 (HER2)-positive breast cancer brain [181]
Emtansine 022 vision on how to tackle T-DXd resistance.
metastases
α-specific class I PI3K inhibitor ap-
proved in combination with fulvestrant
Preclinical and clinical evidence of alpelisib in
for the treatment of PIK3CA-mutated
combination with other anti-cancer agents,
34 Alpelisib, hormone receptor-positive (HR+), hu- Approved [181]
highlighting the potential role of alpelisib in
man epidermal growth factor receptor 2
cancer therapy.
negative (HER2-) metastatic breast
cancer
CDK4/6 blockade and immune check-
GPER belongs to the family of G protein-
point inhibition (eg, programmed death-1
coupled receptors with seven transmembrane
[PD-1]) in ER+/HER2− breast cancer
domains predominantly located on the plasma
- Anastrozole, through multiple mechanisms, including Approved
membrane. Upon binding with ligands, GPER
[181]
upregulation of programmed cell death
activates downstream signaling by stimulating
ligand 1 (PD-L1) and enhanced anti-
Gαs
tumour T-cell activity
Reawakening the Master Switches in Triple-
A topoisomerase II inhibitor, alkylating
Negative Breast Cancer: A Strategic Blueprint
35 Doxorubicin, agents such as cyclophosphamide, a Approved [181]
for Confronting Metastasis and Chemo-
taxane, as an antimicrotubule agent
resistance via MicroRNA-200/205
Elacestrant in ESR1-mutant, endocrine-
Treated HRþ/HER2 mBC, including responsive metastatic breast cancer: should
36 Elacestrant Approved [181]
patients with ESR1-mutated tumors health authorities consider post hoc data to
inform priority access

Fig. (3). Trans-signaling and trans-presentation pSTAT3 classic, IL-6/JAK/STAT3 classic When IL-6 attaches to membrane-bound IL-6Ra, a trimeric receptor
complex containing the signal-transducing subunit gp130 is formed, which results in signaling (left) [44]. For intracellular signaling via the JAK/STAT3 path-
ways, two trimeric IL-6/IL-6Ra/gp130 complexes bind via the D1 domain gp130 to form a hexameric receptor complex. JSKs are drawn to the membrane,
phosphorylating gp130 and S's cytoplasmic tails. (A higher resolution / colour version of this figure is available in the electronic copy of the article).
Recent Prospectives of Cellular Signaling Role for Mammary Gland Anti-Cancer Agents in Medicinal Chemistry, XXXX, Vol. XX, No. XX 13

Fig. (4). Numerous nuclear transcription factors and 100s of cytosolic proteins are phosphorylated by MAP4Ks, MAPK KINASE , MAP3Ks; MAPK stands
mitogen-activation protein kinase, MEK stands for MNK for serine; MSK for mitogen protein kinase; RSK for ribosomal s6 kinase/ threonine-protein kinase
that interaction with MAP kinase. The transcription factors Sp1 and Elk1, proteins having the ETS domains Elk-1, Ets1, cytosolic phospholipase, protein C- ets
1, and cPLA2 A2 [68-70]. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (5). (A) Bcl-2 family member effector proteins(Bax and Bak) oligomerize and pereablize the outer mitochondrial membrane(OMM) upon activator protein
(Did and PUMA) binding cytochrome-C can espace the mitochondria through Bak/Bax pores, leading to caspase cleavage and apoptosis. The Bcl-2 family
antiapoptotic members, Al, Bcl-2, Bcl-xL, Bcl-w, and Mcl-1, inhibit apoptosis via blocking Bak/Bax activation or effector protein oligomerization [76]. Sensi-
tizer proteins (Bad, Bik, and Noxa) interact with antiapoptotic members by sequestering antiapoptotic proteins. (B) When the balance of active Bcl-2 proteins
favors pro-apoptotic over antiapoptotic family members, apoptosis is initiated. (C, D) Proposed models of Mcl-1 expression or activity supporting resistance to
standard chemotherapies or targeted therapies (C) and BH3-mimetics (B) [77]. (A higher resolution / colour version of this figure is available in the electronic
copy of the article).
14 Anti-Cancer Agents in Medicinal Chemistry, XXXX, Vol. XX, No. XX Kashyap et al.

Fig. (6). The androgen receptor (AR), part of the steroid hormone receptor family within the nuclear receptor superfamily, operates as a ligand-dependent tran-
scription factor with various impacts on breast tissue, ranging from physiological changes during puberty and aging to the development and progression of
breast cancer. AR, alongside other receptors like the progesterone receptor (PR) and the glucocorticoid receptor, regulates the expression of specific genes
involved in a range of physiological and pathological processes. These processes include male fertility, cognitive function, physical strength, libido, and the
development of primary and secondary sexual characteristics, such as mammary gland development in both sexes. Additionally, AR is implicated in the onset
and progression of breast and prostate cancers. The receptor's action is dynamic and evolves in stages through a transcriptional or genomic mechanism. In the
absence of hormones, AR remains in the cytoplasm. Molecular chaperones like heat-shock protein 90 (HSP90) aid in protein folding, maintaining AR in a
conformation conducive to high-affinity ligand binding, thereby enhancing its responsiveness to specific ligands [71].

Fig. (7). Genomic mechanism of androgens. (A higher resolution / colour version of this figure is available in the electronic copy of the article).
Recent Prospectives of Cellular Signaling Role for Mammary Gland Anti-Cancer Agents in Medicinal Chemistry, XXXX, Vol. XX, No. XX 15

Fig. (8). Phytochemical Sources used in Breast cancer prevention and treatment. (A higher resolution / colour version of this figure is available in the electron-
ic copy of the article).

MDA-MB-231 human breast cancer cells, thereby confirming their significant impacts were observed in the social and psychological
apoptotic decreased breast cancer carcinogenesis [148]. well-being domains. Nevertheless, ginseng use was evaluated at 6-
and 36-month intervals in subsequent research of 4,149 women
6.3. Ginseng (Panax ginseng) with primary breast cancer who took part in the Shanghai Breast
Cancer Survive research, and the results revealed no improvement
Ginseng is known scientifically as Panax ginseng. This peren- in the survivors' quality of life, particularly in the fields of health,
nial plant is mainly found in China, Korea, Japan, and Russia. Dried society, and psychology [154]. The authors explained the variation
root is one of the uses of this plant. It can treat cancer, among many in responses to the study design and the specific ginseng dosages
other conditions [149]. Research on ginseng's active ingredients has given to breast cancer survivors.
revealed that they either decrease or prevent the growth of tumor
necrosis factor in mouse skin, stop malignant cells from proliferat- 6.4. Black cohosh (Cimicifuga recemosa)
ing and metastasizing, and increase interferon levels and cell differ-
entiation. Ginseng's components may help inhibit other types of The biological source of black cohos is Cimicifuga racemosa.
malignant cell stages. This is a variety of sherb and found in native to eastern forests of
North America. It is most commonly used in radiotherapy and
A Korean study also suggested that ginseng lowers the risk of chemotherapy treatment in Breast cancer patients. For centuries,
cancer in humans. Regarding freshly cut ginseng, its juice, tea, Native Americans have employed black cohosh for various medici-
extract, and dried powder are the most potent and active forms of nal purposes [155]. Additionally, black cohosh can cause issues
ginseng [150]. The potential method of action of ginsenosides on similar to those associated with abortion. This plant was the prima-
cognition is shown by research on animals, biochemistry, mole- ry ingredient in the renowned patent medication Lydia Pinkham's
cules, and cells; nevertheless, the underlying mechanisms remain Vegetable Compound and was included in the pharmacopeia during
conclusively determined. Compiles data from preclinical research the 19th century. Drug stores offer a wide range of black cohosh
on molecular targets implicated in cognitive processes [151]. Those preparations. Herbalists have shown that black cohosh is a safe and
engaged in glutamatergic and acetylcholine (choliner- effective treatment for menopausal symptoms [156]. Many women
gic)neurotransmission are excitatory neurotransmitters in the cen- have discontinued hormone replacement therapy (HRT) on their
tral nervous system (CNS) glutamate, and the activity of ionotropic doctor's advice and switched to black cohosh. Most research has
glutamate receptors is essential for memory and neuronal plastici- focused on the herb's effects on menopausal symptoms. Although
ty.136-266 acetylcholine (cholinergic) receptors have been identi- the precise active ingredients of black cohosh are unknown, triter-
fied as therapeutic targets in a range of neurological disorders, in- pene glycosides are believed to be a crucial component. It also con-
cluding dementia 129 and schizophrenia, as well as modulators of tains small amounts of resins, caffeic, ferulic, and fumaric acids.
memory 127,128 (especially muscarinic) and attention (nicotin- There are uncertainties about black cohosh's estrogenic and anti-
ic).130 Additional significant goals include the control of gene estrogenic properties. Various studies have produced conflicting
expression related to memory formation and neural [152]. results, with some indicating that it either inhibits or promotes can-
cer cell growth in culture [157].
According to studies, cancer patients take ginseng for various
purposes, such as improved quality of life, decreased side effects 6.5. Garlic (Allium sativum)
from chemotherapy, potentially increased effects from chemothera-
peutic medications, and alleviation of cancer diagnosis was signifi- Garlic (Allium sativum) has been used medicinally for centuries
cantly correlated with improved clinical results [153]. The most to treat various illnesses. It involves one hundred or more medici-
16 Anti-Cancer Agents in Medicinal Chemistry, XXXX, Vol. XX, No. XX Kashyap et al.

nally valuable secondary metabolites, such as allicin, alliin, and tumor development .strong antioxidants, and carotenoid compounds
alliinase. Garlic oil contains allicin, an amino acid that becomes exhibit a wide range of therapeutic properties such as the capacity
allicin when crushed into rhizomes [158]. Allicin, which gives sul- to find free radicals, protect cells from oxidative damage, enhance
fur, Ajoene, another molecule that holds sulfur, is present in garlic gap intersections, boost immunity, control enzyme activity, reduce
and oil. While selenium acts as an antioxidant, ajoene slows the the risk of cancer, and boost the body's immune response [169].
development of Cancer. Garlic also contains the bioflavonoid quer-
cetin and cyanidin, which have antioxidant qualities. Garlic's potent 6.9. Echinacea
anticancer properties stem from its high content of organic and
polysulfides—investigations in clinical garlic [159, 160]. The family Asteraceae includes the plant Echinacea. Grown
mostly in the eastern United States and the Great Plains, this fra-
6.6. Vitamin D grant shrub is also grown in Europe. The plant is vacant [170].
Echinacea purpurea, Echinacea angustifolia, and Echinacea pallida
Skin contact with the sun produces vitamin D. A significant are the three species that are most commonly used in herbal medi-
amount of vitamin D is created in the summer by simple hand, arm, cines. Research is where E. purpurea is most frequently used. Pur-
and face contact. Even standing in the sun on the beach until your ple coneflower treatment, Kansas snakeroot, and black Sampson are
skin turns pink is equivalent to taking 20,000 IU of vitamin D2 common names for Echinacea. Researchers have discovered that E.
orally [161]. Our bodies need 1000 IU of vitamin D daily to remain purpurea causes the experimental mice's natural killer cell count to
adequate. Oral absorption is the only way to stabilize vitamin D rise. It is probable that E. purpurea will be employed in the future as
levels when sunlight is absent. Consuming 4,000 IU in one day and an anticancer drug [171].
additional benefits is safe [162]. The active form of vitamin D is
consumed in 4,000 IU daily, with extra benefits. The active form of 6.10. Flax seed
vitamin D possesses anticancer properties. The body's essential
organs can perform their jobs by converting the primary circulating The flax plant's hard-coated, tiny, brown, and golden seeds.
form of vitamin D, 25(OH)2D. Exposure to sunlight stimulates the Every active ingredient is present in this little seed. Omega 3 fatty
local mechanism in all these organs, which converts the circulating acids, lignans, are processed in the gastrointestinal system to create
Form into the hormonal Form. enterolactone and enterodiol. Flax seeds contain more powerful
phytoestrogens than soy products, and eating flax seeds significant-
6.7. Camellia Sinenis (Green Tea) ly alters the way that 2-hydoxyesterone is eliminated in comparison
to soy protein [172]. Lilian Thompson's research group at the Uni-
The fresh leaves and buds of the evergreen Camellia sinensis versity of Toronto demonstrated that ground flax seeds have potent
plant, which have been exposed to heat or hot steam, generate the anticancer properties. Mice were used in the experiment; first, car-
bioactive compounds in green tea [144]. Green tea contains bioac- cinogens were given to the mice, causing cancer. In one set of mice,
tive polyphenols, and the percentage of polyphenols and caffeine in the anticancer properties of flax seed were discovered by including
powdered or liquid extracts varies from 45.0 to 90.0 %. Flavonoids, lignin in the mice's diet.
flavonols, flavanols, and phenolic acids make up polyphenols.
The tumor load has decreased as a result of this experiment.
Green tea leaves include a primary class of flavonoids called cate-
Cancers decreased by flax seeds and secoisolariciresinol diglyco-
chins, which comprise 30 and 42% of the tea's total dry weight. The
side [173]. This scientific team has recently injected human breast
percentages of the catechins are as follows: 13.0%,6.4%,59.0%, and
cancer cells into animals to cause tumors. Mice were given a base-
19.0%, respectively; epicatechin-3-gallatel (ECG), epicate-
line diet for eight weeks following the injection of cancer cells,
chin(EG), and epigallocatechin (3-gallate) [163]. The current cate-
during which time the disease spread 10% flax seed was provided
chins, the most abundant biologically active ingredient in green tea
to increase the growth rate of cancer by 45%. Flaxseeds improve
leaves, epigallocatechin -3-gallate, is between 50 and 70 percent of
mammary gland morphogenesis in mice. When researchers looked
the total [147]. Green glycosides contain flavonols such as apig-
into the mammary glands of the female mice given a diet containing
enin, quercetin, kaempferol, and metrication [164, 165]. In order to
10% flax seeds, they discovered that there were more terminal end
keep an adequate level, our body needs a minimum of 1000 IU of
buds and terminal ducts [174]. They divide epithelial cells more
vitamins every day. The only way to keep vitamin D levels stable
than they should. Every female exhibits more differentiation. After
when there isn't enough sunshine is through oral absorption. Along
carcinogens are injected into the mammary glands, the incidence of
with additional advantages, 4000 IU can be used safely in a single
breast tumours in females is comparatively low. Thus, flax seeds
day. Sunlight exposure stimulates the local systems in all of these
may help female offspring of mice become less susceptible to
organs transforming the circulating form into the hormonal form
carcinogens by increasing the differentiation of their mammary
[166]. Carotenoids: Green herbs with leaves and rose hips contain
tissues, preventing cancers, and reducing the development of
an active ingredient called "carotenoids". These fragrant herbs are
tumors [175].
employed as colouring agents; examples include paprika, annatto,
and saffron. Fruit and vegetable consumption has been associated
6.11. Alovera
with a decrease in the growth of certain tumour kinds. Tumour
incidence is also reduced by diet-induced carotenoid intake. Strong Alovera, also known as aloe barbadensis, belongs to the ap-
antioxidants, carotenoid compounds exhibit a wide range of proximately 300 species strong liliaceae family. Alovera's anti-
therapeutic properties, including the ability to seek out free reactive inflammatory, antioxidant, and antibacterial properties make it
radicals, cytoprotective from oxidative damage, enhance gap well-known for its topical application in managing burn injuries.
intersection, Enhances action of the immune system and also Although aloe vera's exact mechanism of action is unknown, inhibi-
regulate biological enzyme activities [167]. tion of cyclooxygenase is thought to be involved [176, 177]. The
anti-inflammatory and antioxidant properties of aloe vera may be
6.8. Carotenoids enhanced by cyclooxygenase inhibition. Qualities, and as a result, it
can heal wounds more quickly and treat burns. Alovera may also
An ingredient in green, leafy herbs and rose hips is called "ca-
play a role in leukocyte and platelet aggregation, causing a decrease
rotenoids." Certain aromatic herbs, like paprika, annatto, and saf-
in vasoconstriction and contributing to wound healing [178].
fron, are employed as coloring agents. Fruit and vegetable con-
Alovera's mechanism of action enables many pharmacology claims,
sumption has been associated with a decreased risk of tumor growth
leading to a broad range of therapeutic applications, including but
[168]. Dietary consumption of carotenoids also reduces the risk of
not restricted to arthritis, asthma, ulcers, skin gastrointesti-
Recent Prospectives of Cellular Signaling Role for Mammary Gland Anti-Cancer Agents in Medicinal Chemistry, XXXX, Vol. XX, No. XX 17

nal ailments, and candida. In clinical research, alovera's capacity to ER = Estrogen Receptor
lessen the harmful effects of radiation is now being assessed [179].
FAK = Focal Adhesion Kinase
7. DISCUSSION HD = Hinge Domain
Around 25% of all female cancer cases, which are highly com- HRD = Homology-directed Repair
mon in industrialized countries, are breast cancer, the most common IAP = Intrinsic Apoptotic Pathways
type of cancer in women globally. In women globally, breast cancer
ranks as the second most common cause of cancer-related fatalities. IL-6 = Interleukin-6
Compared to other forms of breast cancer, breast cancer has a high- JAKs = Janus Kinase
er global death rate. According to recent research, synthetic deriva-
tives effectively combat MCF-7 cell lines, breast cancer cell lines, LBD = Ligand-binding Domain
and MCF-7 cell lines that are resistant to many drugs. This review mAbs = Monoclonal Antibodies
provides a wealth of information on the mechanism of action of
synthetic derivatives on multidrug-resistant cell lines. This review MAPK = Mitogen-activated Protein Kinase
includes information about how synthetic derivatives affect cancer MDR = Multidrug resistance
cells that have developed multidrug resistance during chemothera-
py. These mechanisms have been linked to increased drug efflux, OMM = Outer Mitochondrial Membrane
genetic and growth factors, DNA repair capacity, and elevated xe- ORF = Open Reading Frame
nobiotic metabolism. Because of this, more research is necessary to
learn more about the effectiveness of synthetic derivatives against PI3K = Phosphatidylinositide-3 Kinase
breast cancer and cell lines that are resistant to several drugs. In PIAS = Phosphatases, Inhibitors of Activated STATs
Palestine, people with breast cancer frequently employ herbal ther-
apies. Herbal remedy use was linked to factors such as educational SERM = Selective Estrogen Receptor Modulator
attainment, length of time from diagnosis, kind of surgery, and use STATs = Signal Transducer and Activator of Transcription
of endocrine medication. It was clear that most users were content
with using natural treatments. The recent perspective of this review TNBC = Triple-negative Breast Cancer
is that we are to find the permanent cure for breast cancer disorder
by the various signaling pathways interlinked with each other be- CONSENT FOR PUBLICATION
cause the researchers target the signal molecule for the temporary
Not applicable.
treatment of the cancers. Still, we reviewed the different signaling
pathways regulated by each other, discussed above in this review.
FUNDING
Also, we reviewed the various anticancer agents used for the treat-
ment of breast cancer during the preceding 20 years, as well as an None.
examination of the different natural sources used for the prevention
and treatment of breast cancer. CONFLICT OF INTEREST

CONCLUSION The authors declare no conflict of interest, financial or other-

wise.
In conclusion, cellular signaling plays a critical role in mamma-
ry gland carcinogenesis, with multiple interconnected pathways and ACKNOWLEDGEMENTS
factors contributing to the initiation and progression of breast can-
cer. Continued research is essential to unravel these signaling net- Declared none.
works' complexities and translate these findings into practical, per-
sonalized treatments for patients. Advances in understanding sig- REFERENCES
naling pathways have led to targeted therapies aimed at specific [1] Curtis, C.; Shah, S.P.; Chin, S.F.; Turashvili, G.; Rueda, O.M.;
molecules within these pathways. These therapies, including inhibi- Dunning, M.J.; Speed, D.; Lynch, A.G.; Samarajiwa, S.; Yuan, Y.;
tors of HER2, PI3K, and PARP, show promise in treating various Gräf, S.; Ha, G.; Haffari, G.; Bashashati, A.; Russell, R.; McKin-
subtypes of breast cancer. Estrogens, progesterone, and growth ney, S.; Langerød, A.; Green, A.; Provenzano, E.; Wishart, G.;
factors such as EGF (epidermal growth factor) and IGF (insulin-like Pinder, S.; Watson, P.; Markowetz, F.; Murphy, L.; Ellis, I.;
growth factor) play pivotal roles in mammary gland development. Purushotham, A.; Børresen-Dale, A.L.; Brenton, J.D.; Tavaré, S.;
Aberrations in the signaling cascades triggered by these molecules Caldas, C.; Aparicio, S. The genomic and transcriptomic architec-
ture of 2,000 breast tumours reveals novel subgroups. Nature,
can contribute to tumorigenesis. Recent studies on cellular signaling 2012, 486(7403), 346-352.
in mammary gland carcinogenesis have provided significant in- http://dx.doi.org/10.1038/nature10983 PMID: 22522925
sights into the complex mechanisms driving breast cancer devel- [2] Subramanian, A.; Tamayo, P.; Mootha, V.K.; Mukherjee, S.; Ebert,
opment and progression. B.L.; Gillette, M.A.; Paulovich, A.; Pomeroy, S.L.; Golub, T.R.;
Lander, E.S.; Mesirov, J.P. Gene set enrichment analysis: A
AUTHORS’ CONTRIBUTIONS knowledge-based approach for interpreting genome-wide expres-
sion profiles. Proc. Natl. Acad. Sci., 2005, 102(43), 15545-15550.
It is hereby acknowledged that all authors have accepted re- http://dx.doi.org/10.1073/pnas.0506580102 PMID: 16199517
sponsibility for the manuscript's content and consented to its sub- [3] Coates, A.S.; Winer, E.P.; Goldhirsch, A.; Gelber, R.D.; Gnant, M.;
mission. They have meticulously reviewed all results and unani- Piccart-Gebhart, M.; Thürlimann, B.; Senn, H.J.; André, F.;
mously approved the final version of the manuscript. Baselga, J.; Bergh, J.; Bonnefoi, H.; Burstein, H.; Cardoso, F.;
Castiglione-Gertsch, M.; Coates, A.S.; Colleoni, M.; Curigliano,
LIST OF ABBREVIATIONS G.; Davidson, N.E.; Di Leo, A.; Ejlertsen, B.; Forbes, J.F.; Gal-
imberti, V.; Gelber, R.D.; Gnant, M.; Goldhirsch, A.; Goodwin, P.;
ADCs = Antibody-drug Conjugates Harbeck, N.; Hayes, D.F.; Huober, J.; Hudis, C.A.; Ingle, J.N.; Jas-
sem, J.; Jiang, Z.; Karlsson, P.; Morrow, M.; Orecchia, R.; Kent
CDK = Cyclin-dependent Kinase Osborne, C.; Partridge, A.H.; de la Peña, L.; Piccart-Gebhart, M.J.;
Pritchard, K.I.; Rutgers, E.J.T.; Sedlmayer, F.; Semiglazov, V.;
ECM = Extra Cellular Matrix
18 Anti-Cancer Agents in Medicinal Chemistry, XXXX, Vol. XX, No. XX Kashyap et al.

Shao, Z-M.; Smith, I.; Thürlimann, B.; Toi, M.; Tutt, A.; Viale, G.; interstitial nephritis antigen (TINag) in cell survival utilizing integ-
von Minckwitz, G.; Watanabe, T.; Whelan, T.; Winer, E.P.; Xu, B. rin αvβ3/focal adhesion kinase (FAK)/phosphatidylinositol 3-
Tailoring therapies—improving the management of early breast kinase (PI3K)/protein kinase B-serine/threonine kinase (AKT) sig-
cancer: St Gallen International Expert Consensus on the Primary naling pathway. J. Biol. Chem., 2019, 294(26), 10379.
Therapy of Early Breast Cancer 2015. Ann. Oncol., 2015, 26(8), http://dx.doi.org/10.1074/jbc.W119.009585 PMID: 31253687
1533-1546. [20] Stinson, B.M.; Loparo, J.J. Repair of DNA Double-Strand Breaks
http://dx.doi.org/10.1093/annonc/mdv221 PMID: 25939896 by the Nonhomologous End Joining Pathway. Annu. Rev. Bio-
[4] Hobday, T.J.; Perez, E.A. Molecularly targeted therapies for breast chem., 2021, 90(1), 137-164.
cancer. Cancer Contr., 2005, 12(2), 73-81. http://dx.doi.org/10.1146/annurev-biochem-080320-110356 PMID:
http://dx.doi.org/10.1177/107327480501200202 PMID: 15855890 33556282
[5] Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, [21] Zhao, H. Mismatch repair deficiency endows tumors with a unique
I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN mutation signature and sensitivity to DNA double-strand breaks.
Estimates of Incidence and Mortality Worldwide for 36 Cancers in Elife, 2014, 3, e02725.
185 Countries. CA Cancer J. Clin., 2021, 71(3), 209-249. http://dx.doi.org/10.7554/eLife.02725
http://dx.doi.org/10.3322/caac.21660 PMID: 33538338 [22] Concannon, K.; Morris, B.B.; Gay, C.M.; Byers, L.A. Combining
[6] Kashyap, M.K.; Mangrulkar, S.V.; Kushwaha, S.; Ved, A.; Kale, targeted DNA repair inhibition and immune-oncology approaches
M.B.; Wankhede, N.L.; Taksande, B.G.; Upaganlawar, A.B.; Ume- for enhanced tumor control. Mol. Cell, 2023, 83(5), 660-680.
kar, M.J.; Koppula, S.; Kopalli, S.R. Recent Perspectives on Cardi- http://dx.doi.org/10.1016/j.molcel.2022.12.031 PMID: 36669489
ovascular Toxicity Associated with Colorectal Cancer Drug Thera- [23] Chedgy, E.C.P.; Black, P.C. Moving Beyond the Androgen Recep-
py. Pharmaceuticals (Basel), 2023, 16(10), 1441. tor in Advanced Prostate Cancer Commentary on: DNA-repair De-
http://dx.doi.org/10.3390/ph16101441 PMID: 37895912 fects and Olaparib in Metastatic Prostate Cancer. Urology, 2016,
[7] Zhang, X.; Sun, C.; Wan, J.; Zhang, X.; Jia, Y.; Zhou, C. Com- 89, 10-11.
partmentalized activities of HMGCS1 control cervical cancer radi- http://dx.doi.org/10.1016/j.urology.2015.12.002 PMID: 26723184
osensitivity. Cell. Signal., 2023, 101, 110507. [24] Hakem, R. DNA-damage repair; the good, the bad, and the ugly.
http://dx.doi.org/10.1016/j.cellsig.2022.110507 PMID: 36328117 EMBO J., 2008, 27(4), 589-605.
[8] Shen, M.; Cai, R.; Li, Z.; Chen, X.; Xie, J. The Molecular Mecha- http://dx.doi.org/10.1038/emboj.2008.15 PMID: 18285820
nism of Yam Polysaccharide Protected H2O2-Induced Oxidative [25] Jackson, S.P.; Bartek, J. The DNA-damage response in human
Damage in IEC-6 Cells. Foods, 2023, 12(2), 262. biology and disease. Nature, 2009, 461(7267), 1071-1078.
http://dx.doi.org/10.3390/foods12020262 PMID: 36673354 http://dx.doi.org/10.1038/nature08467 PMID: 19847258
[9] Serda, M. Synthesis and biological activity of new thiosemicarba- [26] Le, J.; Perez, E.; Nemzow, L.; Gong, F. Role of deubiquitinases in
zone analogues of iron chelators., Bioorg. Chem., 2013, 87, 155- DNA damage response. DNA Repair (Amst.), 2019, 76, 89-98.
162. http://dx.doi.org/10.1016/j.dnarep.2019.02.011 PMID: 30831436
[10] Discher, D.E.; Mooney, D.J.; Zandstra, P.W. Growth factors, ma- [27] Zhou, Y.; Mouw, K.W. DNA repair deficiency and the immune
trices, and forces combine and control stem cells. Science, 2009, microenvironment: A pathways perspective. DNA Repair (Amst.),
324(5935), 1673-1677. 2024, 133, 103594.
http://dx.doi.org/10.1126/science.1171643 http://dx.doi.org/10.1016/j.dnarep.2023.103594 PMID: 37980867
[11] Eddy, A.A. Molecular insights into renal interstitial fibrosis. J. Am. [28] Ring, A.; Kim, Y.M.; Kahn, M. Wnt/catenin signaling in adult stem
Soc. Nephrol., 1996, 7(12), 2495-2508. cell physiology and disease. Stem Cell Rev., 2014, 10(4), 512-525.
http://dx.doi.org/10.1681/ASN.V7122495 PMID: 8989727 http://dx.doi.org/10.1007/s12015-014-9515-2 PMID: 24825509
[12] Fukui, F.; Hayashi, S.; Yamaguchi, Y. Heregulin controls ERα and [29] Vilchez, V.; Turcios, L.; Marti, F.; Gedaly, R. Targeting Wnt/β-
HER2 signaling in mammospheres of ERα-positive breast cancer catenin pathway in hepatocellular carcinoma treatment. World J.
cells and interferes with the efficacy of molecular targeted therapy. Gastroenterol., 2016, 22(2), 823-832.
J. Steroid Biochem. Mol. Biol., 2020, 201, 105698. http://dx.doi.org/10.3748/wjg.v22.i2.823 PMID: 26811628
http://dx.doi.org/10.1016/j.jsbmb.2020.105698 PMID: 32404282 [30] Li, Y.; Li, Y.; Yang, Y.; Deng, Y.; Ni, X.; Zhao, B.; Yan, Z.; He,
[13] Reiske, H.R.; Zhao, J.; Han, D.C.; Cooper, L.A.; Guan, J.L. Analy- W.; Li, Y.; Li, S.; Liu, L.; Lu, D. Synergistic efficacy of PI3Kδ in-
sis of FAK‐associated signaling pathways in the regulation of cell hibitor with anti-PD-1 mAbs in immune-humanized PDX model of
cycle progression. FEBS Lett., 2000, 486(3), 275-280. endocrine resistance hormone receptor-positive advanced breast
http://dx.doi.org/10.1016/S0014-5793(00)02295-X PMID: cancer. Heliyon, 2023, 9(8), e18498.
11119718 http://dx.doi.org/10.1016/j.heliyon.2023.e18498 PMID: 37533997
[14] van de Water, B.; Nagelkerke, J.F.; Stevens, J.L. Dephosphoryla- [31] Slamon, D.J.; Neven, P.; Chia, S.; Fasching, P.A.; De Laurentiis,
tion of focal adhesion kinase (FAK) and loss of focal contacts pre- M.; Im, S.A.; Petrakova, K.; Bianchi, G.V.; Esteva, F.J.; Martín,
cede caspase-mediated cleavage of FAK during apoptosis in renal M.; Nusch, A.; Sonke, G.S.; De la Cruz-Merino, L.; Beck, J.T.;
epithelial cells. J. Biol. Chem., 1999, 274(19), 13328-13337. Pivot, X.; Vidam, G.; Wang, Y.; Rodriguez Lorenc, K.; Miller, M.;
http://dx.doi.org/10.1074/jbc.274.19.13328 PMID: 10224094 Taran, T.; Jerusalem, G. Phase III randomized study of ribociclib
[15] Ning, L. Focal Adhesion Kinase (FAK) is a downstream effector of and fulvestrant in hormone receptor-positive, human epidermal
the Raf-1 signal transduction pathway in gastrointestinal carcinoid growth factor receptor 2-negative advanced breast cancer:
cancer cells. J. Surg. Res., 2008, 144(2), 239. MONALEESA-3. J. Clin. Oncol., 2018, 36(24), 2465-2472.
[16] Lim, S.T.; Chen, X.L.; Lim, Y.; Hanson, D.A.; Vo, T.T.; Hower- http://dx.doi.org/10.1200/JCO.2018.78.9909 PMID: 29860922
ton, K.; Larocque, N.; Fisher, S.J.; Schlaepfer, D.D.; Ilic, D. Nucle- [32] Dean, J.L.; Thangavel, C.; McClendon, A.K.; Reed, C.A.; Knud-
ar FAK promotes cell proliferation and survival through FERM- sen, E.S. Therapeutic CDK4/6 inhibition in breast cancer: key
enhanced p53 degradation. Mol. Cell, 2008, 29(1), 9-22. mechanisms of response and failure. Oncogene, 2010, 29(28),
http://dx.doi.org/10.1016/j.molcel.2007.11.031 PMID: 18206965 4018-4032.
[17] Xie, P.; Kondeti, V.K.; Lin, S.; Haruna, Y.; Raparia, K.; Kanwar, http://dx.doi.org/10.1038/onc.2010.154 PMID: 20473330
Y.S. Role of extracellular matrix renal tubulo-interstitial nephritis [33] Wekking, D. CDK4/6 inhibition in hormone receptor-
antigen (TINag) in cell survival utilizing integrin (al- positive/HER2-negative breast cancer: Biological and clinical as-
pha)vbeta3/focal adhesion kinase (FAK)/phosphatidylinositol 3- pects. Cytokine Growth Factor Rev., 2023, 75, 57-64.
kinase (PI3K)/protein kinase B-serine/threonine kinase (AKT) sig- http://dx.doi.org/10.1016/j.cytogfr.2023.10.001
naling pathway. J. Biol. Chem., 2011, 286(39), 34131-34146. [34] Asif, H.; Barnett, S.D.; Saxon, D.; Younis, H.; Buxton, I.L.O. β3
http://dx.doi.org/10.1074/jbc.M111.241778 PMID: 21795690 adrenergic receptor activation modulates connexin 43 activity to re-
[18] Golubovskaya, V.M.; Finch, R.; Kweh, F.; Massoll, N.A.; Camp- lax human myometrium. Cell. Signal., 2023, 106, 110640.
bell-Thompson, M.; Wallace, M.R.; Cance, W.G. p53 regulates http://dx.doi.org/10.1016/j.cellsig.2023.110640 PMID: 36841274
FAK expression in human tumor cells. Mol. Carcinog., 2008, [35] Ghauri, M.A.; Raza, A.; Hayat, U.; Atif, N.; Iqbal, H.M.N.; Bilal,
47(5), 373-382. M. Mechanistic insights expatiating the biological role and regula-
http://dx.doi.org/10.1002/mc.20395 PMID: 17999388 tory implications of estrogen and HER2 in breast cancer metastasis.
[19] Xie, P.; Kondeti, V.K.; Lin, S.; Haruna, Y.; Raparia, K.; Kanwar, Biochim. Biophys. Acta, Gen. Subj., 2022, 1866(5), 130113.
Y.S. Withdrawal: Role of extracellular matrix renal tubulo- http://dx.doi.org/10.1016/j.bbagen.2022.130113 PMID: 35202768
Recent Prospectives of Cellular Signaling Role for Mammary Gland Anti-Cancer Agents in Medicinal Chemistry, XXXX, Vol. XX, No. XX 19

[36] Dhiwar, P.S.; Matada, G.S.P.; Raghavendra, N.M.; Ghara, A.; [51] Xin, P.; Xu, X.; Deng, C.; Liu, S.; Wang, Y.; Zhou, X.; Ma, H.;
Singh, E.; Abbas, N.; Andhale, G.S.; Shenoy, G.P.; Sasmal, P. Cur- Wei, D.; Sun, S. The role of JAK/STAT signaling pathway and its
rent updates on EGFR and HER2 tyrosine kinase inhibitors for the inhibitors in diseases. Int. Immunopharmacol., 2020, 80, 106210.
breast cancer. Med. Chem. Res., 2022, 31(9), 1401-1413. http://dx.doi.org/10.1016/j.intimp.2020.106210 PMID: 31972425
http://dx.doi.org/10.1007/s00044-022-02934-7 [52] Groner, B.; von Manstein, V. Jak Stat signaling and cancer: Oppor-
[37] Bartholomeusz, C.; Gonzalez-Angulo, A.M.; Liu, P.; Hayashi, N.; tunities, benefits and side effects of targeted inhibition. Mol. Cell.
Lluch, A.; Ferrer-Lozano, J.; Hortobágyi, G.N. High ERK protein Endocrinol., 2017, 451, 1-14.
expression levels correlate with shorter survival in triple-negative http://dx.doi.org/10.1016/j.mce.2017.05.033 PMID: 28576744
breast cancer patients. Oncologist, 2012, 17(6), 766-774. [53] Uluer, E.T.; Aydemir, I.; Inan, S.; Ozbilgin, K.; Vatansever, H.S.
http://dx.doi.org/10.1634/theoncologist.2011-0377 PMID: Effects of 5-fluorouracil and gemcitabine on a breast cancer cell
22584435 line (MCF-7) via the JAK/STAT pathway. Acta Histochem., 2012,
[38] Tavčar Kunstič, T.; Debeljak, N.; Fon Tacer, K. Heterogeneity in 114(7), 641-646.
hormone-dependent breast cancer and therapy: Steroid hormones, http://dx.doi.org/10.1016/j.acthis.2011.11.010 PMID: 22172707
HER2, melanoma antigens, and cannabinoid receptors. Adv. Can- [54] Dinakar, Y.H.; Kumar, H.; Mudavath, S.L.; Jain, R.; Ajmeer, R.;
cer Biol. Metastasis, 2023, 7, 100086. Jain, V. Role of STAT3 in the initiation, progression, proliferation
http://dx.doi.org/10.1016/j.adcanc.2022.100086 and metastasis of breast cancer and strategies to deliver JAK and
[39] Terán, S.; Alva, M.; Tolosa, P.; Rey-Cárdenas, M.; Madariaga, A.; STAT3 inhibitors. Life Sci., 2022, 309, 120996.
Lema, L.; Ruano, Y.; Manso, L.; Ciruelos, E.; Sánchez-Bayona, R. http://dx.doi.org/10.1016/j.lfs.2022.120996 PMID: 36170890
Analysis of the association of HER-2 low carcinomas and PAM50 [55] Mali, S.B. Review of STAT3 (Signal Transducers and Activators
assay in hormone receptor positive early-stage breast cancer. of Transcription) in head and neck cancer. Oral Oncol., 2015,
Breast, 2023, 71, 42-46. 51(6), 565-569.
http://dx.doi.org/10.1016/j.breast.2023.07.009 PMID: 37481795 http://dx.doi.org/10.1016/j.oraloncology.2015.03.004 PMID:
[40] Maher, P.; Dargusch, R.; Bodai, L.; Gerard, P.E.; Purcell, J.M.; 25817923
Marsh, J.L. ERK activation by the polyphenols fisetin and resvera- [56] Zhang, H.; Wang, Y.; Chen, X.; Zhang, A.; Hou, L.; Hong, J.; Liu,
trol provides neuroprotection in multiple models of Huntington’s J.; Liu, Z.; Yang, P. Targeting epithelial cell-derived TWIST1 alle-
disease. Hum. Mol. Genet., 2011, 20(2), 261-270. viates allergic asthma. Cell. Signal., 2023, 102, 110552.
http://dx.doi.org/10.1093/hmg/ddq460 PMID: 20952447 http://dx.doi.org/10.1016/j.cellsig.2022.110552 PMID: 36481410
[41] Acosta-Casique, A.; Montes-Alvarado, J.B.; Barragán, M.; Lar- [57] Brooks, A.J.; Putoczki, T. Jak-stat signalling pathway in cancer.
rauri-Rodríguez, K.A.; Perez-Gonzalez, A.; Delgado-Magallón, A.; Cancers (Basel), 2020, 12(7), 1971.
Millán-Perez-Peña, L.; Rosas-Murrieta, N.H.; Maycotte, P. ERK http://dx.doi.org/10.3390/cancers12071971 PMID: 32698360
activation modulates invasiveness and Reactive Oxygen Species [58] Rojas-Sanchez, G.; García-Miranda, A.; Montes-Alvarado, J.B.;
(ROS) production in triple negative breast cancer cell lines. Cell. Cotzomi-Ortega, I.; Sarmiento-Salinas, F.L.; Jimenez-Ignacio,
Signal., 2023, 101, 110487. E.E.; Ramírez-Ramírez, D.; Romo-Rodríguez, R.E.; Reyes-Leyva,
http://dx.doi.org/10.1016/j.cellsig.2022.110487 PMID: 36216165 J.; Vallejo-Ruiz, V.; Pazos-Salazar, N.G.; Maycotte, P. Chloro-
[42] Bogoyevitch, M.A.; Court, N.W. Counting on mitogen-activated quine Induces ROS-mediated Macrophage Migration Inhibitory
protein kinases—ERKs 3, 4, 5, 6, 7 and 8. Cell. Signal., 2004, Factor Secretion and Epithelial to Mesenchymal Transition in ER-
16(12), 1345-1354. positive Breast Cancer Cell Lines. J. Mammary Gland Biol. Neo-
http://dx.doi.org/10.1016/j.cellsig.2004.05.004 PMID: 15381250 plasia, 2021, 26(4), 341-355.
[43] Deng, J.; Wang, H.; Liang, Y.; Zhao, L.; Li, Y.; Yan, Y.; Zhao, H.; http://dx.doi.org/10.1007/s10911-021-09503-5 PMID: 34813005
Zhang, X.; Zou, F. miR-15a-5p enhances the malignant phenotypes [59] Zhang, L.; Xu, L.; Wang, Y.; Zhang, X.; Xue, T.; Sun, Q.; Tang,
of colorectal cancer cells through the STAT3/TWIST1 and H.; Li, M.; Cao, X.; Shi, F.; Zhang, G.; Zhang, S.; Hu, Z. Histone
PTEN/AKT signaling pathways by targeting SIRT4. Cell. Signal., methyltransferase Setdb1 mediates osteogenic differentiation by
2023, 101, 110517. suppressing the expression of miR-212-3p under mechanical un-
http://dx.doi.org/10.1016/j.cellsig.2022.110517 PMID: 36332797 loading. Cell. Signal., 2023, 102, 110554.
[44] Wylaź, M.; Kaczmarska, A.; Pajor, D.; Hryniewicki, M.; Gil, D.; http://dx.doi.org/10.1016/j.cellsig.2022.110554 PMID: 36476391
Dulińska-Litewka, J. Exploring the role of PI3K/AKT/mTOR in- [60] Serasinghe, M.N.; Wieder, S.Y.; Renault, T.T.; Elkholi, R.; Asciol-
hibitors in hormone-related cancers: A focus on breast and prostate la, J.J.; Yao, J.L.; Jabado, O.; Hoehn, K.; Kageyama, Y.; Sesaki,
cancer. Biomed. Pharmacother., 2023, 168, 115676. H.; Chipuk, J.E. Mitochondrial division is requisite to RAS-
http://dx.doi.org/10.1016/j.biopha.2023.115676 PMID: 37832401 induced transformation and targeted by oncogenic MAPK pathway
[45] Ortega, M.A.; Fraile-Martínez, O.; Asúnsolo, Á.; Buján, J.; García- inhibitors. Mol. Cell, 2015, 57(3), 521-536.
Honduvilla, N.; Coca, S. Signal Transduction Pathways in Breast http://dx.doi.org/10.1016/j.molcel.2015.01.003 PMID: 25658204
Cancer: The Important Role of PI3K/Akt/mTOR. J. Oncol., 2020, [61] Son, Y.; Kim, S.; Chung, H.T.; Pae, H.O. Reactive oxygen species
2020, 1-11. in the activation of MAP kinases. Methods Enzymol., 2013, 528,
http://dx.doi.org/10.1155/2020/9258396 PMID: 32211045 27-48.
[46] Zhou, Y.; Santini, D.; Rood, M.; Bluestein, L.; Mitchell, G.; Ste- http://dx.doi.org/10.1016/B978-0-12-405881-1.00002-1 PMID:
phens, T.; Ward, J. An assessment of causes of PEV success across 23849857
U.S. metro areas. World Electric Vehicle Journal, 2016, 8(4), 818- [62] Chakraborty, J.; Chakraborty, S.; Chakraborty, S.; Narayan, M.N.
830. Entanglement of MAPK pathways with gene expression and its
http://dx.doi.org/10.3390/wevj8040818 omnipresence in the etiology for cancer and neurodegenerative dis-
[47] Chung, E.; Kondo, M. Role of Ras/Raf/MEK/ERK signaling in orders. Biochim. Biophys. Acta. Gene Regul. Mech., 2023, 1866(4),
physiological hematopoiesis and leukemia development. Immunol. 194988.
Res., 2011, 49(1-3), 248-268. http://dx.doi.org/10.1016/j.bbagrm.2023.194988 PMID: 37739217
http://dx.doi.org/10.1007/s12026-010-8187-5 PMID: 21170740 [63] Zhao, S.; Gu, T.; Weng, K.; Zhang, Y.; Cao, Z.; Zhang, Y.; Zhao,
[48] Pencik, J.; Pham, H.T.T.; Schmoellerl, J.; Javaheri, T.; Schlederer, W.; Chen, G.; Xu, Q. Phosphoproteome Reveals Extracellular
M.; Culig, Z.; Merkel, O.; Moriggl, R.; Grebien, F.; Kenner, L. Regulated Protein Kinase Phosphorylation Mediated by Mitogen-
JAK-STAT signaling in cancer: From cytokines to non-coding ge- Activated Protein Kinase Kinase-Regulating Granulosa Cell Apop-
nome. Cytokine, 2016, 87, 26-36. tosis in Broody Geese. Int. J. Mol. Sci., 2023, 24(15), 12278.
http://dx.doi.org/10.1016/j.cyto.2016.06.017 PMID: 27349799 http://dx.doi.org/10.3390/ijms241512278 PMID: 37569653
[49] Christy, J.; Priyadharshini, L. Differential expression analysis of [64] Carneiro, T.J.; Carvalho, A.L.M.B.; Vojtek, M.; Carmo, I.F.;
JAK/STAT pathway related genes in breast cancer. Meta Gene, Marques, M.P.M.; Diniz, C.; Gil, A.M. Disclosing a metabolic sig-
2018, 16, 122-129. nature of cisplatin resistance in MDA-MB-231 triple-negative
http://dx.doi.org/10.1016/j.mgene.2018.02.008 breast cancer cells by NMR metabolomics. Cancer Cell Int., 2023,
[50] Morris, R.; Kershaw, N.J.; Babon, J.J. The molecular details of 23(1), 310.
cytokine signaling via the JAK/STAT pathway. Protein Sci., 2018, http://dx.doi.org/10.1186/s12935-023-03124-0 PMID: 38057765
27(12), 1984-2009.
http://dx.doi.org/10.1002/pro.3519 PMID: 30267440
20 Anti-Cancer Agents in Medicinal Chemistry, XXXX, Vol. XX, No. XX Kashyap et al.

[65] Yang, S.H.; Sharrocks, A.D.; Whitmarsh, A.J. Transcriptional [80] Iacopetta, D.; Rechoum, Y.; Fuqua, S.A.W. The role of androgen
regulation by the MAP kinase signaling cascades. Gene, 2003, receptor in breast cancer. Drug Discov. Today Dis. Mech., 2012,
320(1–2), 3-21. 9(1-2), e19-e27.
http://dx.doi.org/10.1016/S0378-1119(03)00816-3 PMID: http://dx.doi.org/10.1016/j.ddmec.2012.11.003 PMID: 26568765
14597384 [81] Li, X.; Chang, Y.; Shen, W.; Huang, G.; Hu, N.; Lv, H.; Jin, M.
[66] Braicu, C.; Buse, M.; Busuioc, C.; Drula, R.; Gulei, D.; Raduly, L.; miR-138 from ADSC Exo accelerates wound healing by targeting
Rusu, A.; Irimie, A.; Atanasov, A.G.; Slaby, O.; Ionescu, C.; Ber- SIRT1/PTEN pathway to promote angiogenesis and fibrosis. Cell.
indan-Neagoe, I. A comprehensive review on MAPK: A promising Signal., 2023, 111, 110843.
therapeutic target in cancer. Cancers (Basel), 2019, 11(10), 1618. http://dx.doi.org/10.1016/j.cellsig.2023.110843 PMID: 37544635
http://dx.doi.org/10.3390/cancers11101618 PMID: 31652660 [82] Abraham, J.; Ocen, J.; Staffurth, J. Hormonal therapy for cancer.
[67] Morrison, D.K.; Davis, R.J. Regulation of MAP kinase signaling Medicine (Abingdon), 2023, 51(1), 28-31.
modules by scaffold proteins in mammals. Annu. Rev. Cell Dev. http://dx.doi.org/10.1016/j.mpmed.2022.10.017
Biol., 2003, 19(1), 91-118. [83] khanam, R.; Hejazi, I.I.; Shahabuddin, S.; Bhat, A.R.; Athar, F.
http://dx.doi.org/10.1146/annurev.cellbio.19.111401.091942 Pharmacokinetic evaluation, molecular docking and in vitro biolog-
PMID: 14570565 ical evaluation of 1, 3, 4-oxadiazole derivatives as potent antioxi-
[68] Miyata, Y.; Nishida, E. Distantly related cousins of MAP kinase: dants and STAT3 inhibitors. J. Pharm. Anal., 2019, 9(2), 133-141.
biochemical properties and possible physiological functions. Bio- http://dx.doi.org/10.1016/j.jpha.2018.12.002 PMID: 31011470
chem. Biophys. Res. Commun., 1999, 266(2), 291-295. [84] Cortés, J.; Kim, S.B.; Chung, W.P.; Im, S.A.; Park, Y.H.; Hegg, R.;
http://dx.doi.org/10.1006/bbrc.1999.1705 PMID: 10600495 Kim, M.H.; Tseng, L.M.; Petry, V.; Chung, C.F.; Iwata, H.; Hamil-
[69] Chang, L.; Karin, M. Mammalian MAP kinase signalling cascades. ton, E.; Curigliano, G.; Xu, B.; Huang, C.S.; Kim, J.H.; Chiu,
Nature, 2001, 410(6824), 37-40. J.W.Y.; Pedrini, J.L.; Lee, C.; Liu, Y.; Cathcart, J.; Bako, E.; Ver-
http://dx.doi.org/10.1038/35065000 PMID: 11242034 ma, S.; Hurvitz, S.A. Trastuzumab Deruxtecan versus Trastuzumab
[70] Kyriakis, J.M.; Avruch, J. Mammalian mitogen-activated protein Emtansine for Breast Cancer. N. Engl. J. Med., 2022, 386(12),
kinase signal transduction pathways activated by stress and in- 1143-1154.
flammation. Physiol. Rev., 2001, 81(2), 807-869. http://dx.doi.org/10.1056/NEJMoa2115022 PMID: 35320644
http://dx.doi.org/10.1152/physrev.2001.81.2.807 PMID: 11274345 [85] Kunte, S.; Abraham, J.; Montero, A.J. Novel HER2–targeted thera-
[71] de Paula, C.A.A.; Coulson-Thomas, V.J.; Ferreira, J.G.; Maza, pies for HER2–positive metastatic breast cancer. Cancer, 2020,
P.K.; Suzuki, E.; Nakahata, A.M.; Nader, H.B.; Sampaio, M.U.; 126(19), 4278-4288.
Oliva, M.L.V. Enterolobium contortisiliquum trypsin inhibitor http://dx.doi.org/10.1002/cncr.33102 PMID: 32721042
(EcTI), a plant proteinase inhibitor, decreases in vitro cell adhesion [86] Tan, B.B.J-W.; Mai, A.S.; Lee, S.J-Y.; Tan, E-K. Tamoxifen in
and invasion by inhibition of Src protein-focal adhesion kinase breast cancer and risk of Parkinson’s disease: A meta-analysis. Am.
(FAK) signaling pathways. J. Biol. Chem., 2012, 287(1), 170-182. J. Med. Sci., 2023, •••
http://dx.doi.org/10.1074/jbc.M111.263996 PMID: 22039045 http://dx.doi.org/10.1016/j.amjms.2023.11.003 PMID: 37993099
[72] Weinberg, R.A. The retinoblastoma protein and cell cycle control. [87] Kale, V.P.; Gilhooley, P.J.; Phadtare, S.; Nabavizadeh, A.; Pandey,
Cell, 1995, 81(3), 323-330. M.K. Role of gambogic acid in chemosensitization of cancer. In:
http://dx.doi.org/10.1016/0092-8674(95)90385-2 PMID: 7736585 Role Nutraceuticals Cancer Chemosensitization; Academic Press,
[73] Lei, C.; Du, F.; Sun, L.; Li, T.; Li, T.; Min, Y.; Nie, A.; Wang, X.; 2017; Vol.2, pp. 151-167.
Geng, L.; Lu, Y.; Zhao, X.; Shi, Y.; Fan, D. miR-143 and miR-145 http://dx.doi.org/10.1016/B978-0-12-812373-7.00008-5
inhibit gastric cancer cell migration and metastasis by suppressing [88] Willson, M.L.; Burke, L.; Ferguson, T.; Ghersi, D.; Nowak, A.K.;
MYO6. Cell Death Dis., 2017, 8(10), e3101. Wilcken, N. Taxanes for adjuvant treatment of early breast cancer.
http://dx.doi.org/10.1038/cddis.2017.493 PMID: 29022908 Cochrane Database Syst Rev., 2019, 9(9), CD004421.
[74] Sanchez, E.F.; Schneider, F.S.; Yarleque, A.; Borges, M.H.; Rich- http://dx.doi.org/10.1002/14651858.CD004421.pub3
ardson, M.; Figueiredo, S.G.; Evangelista, K.S.; Eble, J.A. The [89] Kumari, P.; Dang, S. Dual drug loaded nanostructured lipid carrier
novel metalloproteinase atroxlysin-I from Peruvian Bothrops atrox for cytotoxic effect against breast cancer - a drug repurposing ap-
(Jergón) snake venom acts both on blood vessel ECM and platelets. proach. Surf. Interfaces, 2023, 40, 103138.
Arch. Biochem. Biophys., 2010, 496(1), 9-20. http://dx.doi.org/10.1016/j.surfin.2023.103138
http://dx.doi.org/10.1016/j.abb.2010.01.010 PMID: 20102699 [90] Li, Y.; Wang, P.; Zou, Z.; Pan, Q.; Li, X.; Liang, Z.; Li, L.; Lin, Y.;
[75] hang, H.J. Twist2 promotes kidney cancer cell proliferation and Peng, X.; Zhang, R.; Tian, H.; Han, L. Ginsenoside (20S)-
invasion via regulating ITGA6 and CD44 expression in the ECM- protopanaxatriol induces non-protective autophagy and apoptosis
receptor-interaction pathway. Biomed. Pharmacother, 2016, 81, by inhibiting Akt/mTOR signaling pathway in triple-negative
453-459. breast cancer cells. Biochem. Biophys. Res. Commun., 2021, 583,
http://dx.doi.org/10.1016/j.biopha.2016.02.042 184-191.
[76] Fickova, M.; Macho, L.; Brtko, J. A comparison of the effects of http://dx.doi.org/10.1016/j.bbrc.2021.10.067 PMID: 34749235
tributyltin chloride and triphenyltin chloride on cell proliferation, [91] Robinson, D.R.; Wu, Y.M.; Vats, P.; Su, F.; Lonigro, R.J.; Cao, X.;
proapoptotic p53, Bax, and antiapoptotic Bcl-2 protein levels in Kalyana-Sundaram, S.; Wang, R.; Ning, Y.; Hodges, L.; Gursky,
human breast cancer MCF-7 cell line. Toxicol. In Vitro, 2015, A.; Siddiqui, J.; Tomlins, S.A.; Roychowdhury, S.; Pienta, K.J.;
29(4), 727-731. Kim, S.Y.; Roberts, J.S.; Rae, J.M.; Van Poznak, C.H.; Hayes,
http://dx.doi.org/10.1016/j.tiv.2015.02.007 PMID: 25743928 D.F.; Chugh, R.; Kunju, L.P.; Talpaz, M.; Schott, A.F.; Chin-
[77] León-Buitimea, A.; Rodríguez-Fragoso, L.; Lauer, F.T.; Bowles, naiyan, A.M. Activating ESR1 mutations in hormone-resistant
H.; Thompson, T.A.; Burchiel, S.W. Ethanol-induced oxidative metastatic breast cancer. Nat. Genet., 2013, 45(12), 1446-1451.
stress is associated with EGF receptor phosphorylation in MCF- http://dx.doi.org/10.1038/ng.2823 PMID: 24185510
10A cells overexpressing CYP2E1. Toxicol. Lett., 2012, 209(2), [92] Ibrahim, M.Y.; Hashim, N.M.; Omer, F.A.A.; Abubakar, M.S.;
161-165. Mohammed, H.A.; Salama, S.M.; Jayash, S.N. Potential Antitumor
http://dx.doi.org/10.1016/j.toxlet.2011.12.009 PMID: 22222162 Effect of α-Mangostin against Rat Mammary Gland Tumors In-
[78] Rajarajan, S.; Snijesh, V.P.; Anupama, C.E.; Nair, M.G.; Mavatkar, duced by LA7 Cells. Int. J. Mol. Sci., 2023, 24(12), 10283.
A.D.; Naidu, C.M.; Patil, S.; Nimbalkar, V.P.; Alexander, A.; Pil- http://dx.doi.org/10.3390/ijms241210283 PMID: 37373429
lai, M.; Jolly, M.K.; Sabarinathan, R.; Ramesh, R.S.; Bs, S.; Prab- [93] Dank, M. The role of aromasin in the hormonal therapy of breast
hu, J.S. An androgen receptor regulated gene score is associated cancer. Pathol. Oncol. Res., 2002, 8(2), 87-92.
with epithelial to mesenchymal transition features in triple negative http://dx.doi.org/10.1007/BF03033716
breast cancers. Transl. Oncol., 2023, 37, 101761. [94] Kalous, O.; Conklin, D.; Desai, A.J.; O’Brien, N.A.; Ginther, C.;
http://dx.doi.org/10.1016/j.tranon.2023.101761 PMID: 37603927 Anderson, L.; Cohen, D.J.; Britten, C.D.; Taylor, I.; Christensen,
[79] Sharifi, M.N.; O’Regan, R.M.; Wisinski, K.B. Is the Androgen J.G.; Slamon, D.J.; Finn, R.S. Dacomitinib (PF-00299804), an irre-
Receptor a Viable Target in Triple Negative Breast Cancer in 5 versible Pan-HER inhibitor, inhibits proliferation of HER2-
Years? Clin. Breast Cancer, 2023, 23(8), 813-824. amplified breast cancer cell lines resistant to trastuzumab and lapa-
http://dx.doi.org/10.1016/j.clbc.2023.06.009 PMID: 37419745 tinib. Mol. Cancer Ther., 2012, 11(9), 1978-1987.
Recent Prospectives of Cellular Signaling Role for Mammary Gland Anti-Cancer Agents in Medicinal Chemistry, XXXX, Vol. XX, No. XX 21

http://dx.doi.org/10.1158/1535-7163.MCT-11-0730 PMID: cancer): Preclinical and clinical evidences. Biomed. Pharmacother.,

22761403 2023, 159, 114183.
[95] Wang, Y.; Zhou, D.; Phung, S.; Masri, S.; Smith, D.; Chen, S. http://dx.doi.org/10.1016/j.biopha.2022.114183 PMID: 36641927
SGK3 is an estrogen-inducible kinase promoting estrogen-mediated [107] Ueda, A.; Oikawa, K.; Fujita, K.; Ishikawa, A.; Sato, E.; Ishikawa,
survival of breast cancer cells. Mol. Endocrinol., 2011, 25(1), 72- T.; Kuroda, M.; Kanekura, K. Therapeutic potential of PLK1 inhi-
82. bition in triple-negative breast cancer. Lab. Invest., 2019, 99(9),
http://dx.doi.org/10.1210/me.2010-0294 PMID: 21084382 1275-1286.
[96] Hurvitz, S.A.; Bardia, A.; Quiroga, V.; Park, Y.H.; Blancas, I.; http://dx.doi.org/10.1038/s41374-019-0247-4 PMID: 30996295
Alonso-Romero, J.L.; Vasiliev, A.; Adamchuk, H.; Salgado, M.; [108] Muller, M. 5-fluorouracil kinetics in the interstitial tumor space:
Yardley, D.A.; Berzoy, O.; Zamora-Auñón, P.; Chan, D.; Spera, Clinical response in breast cancer patients. Cancer Res., 57, 2598-
G.; Xue, C.; Ferreira, E.; Badovinac Crnjevic, T.; Pérez-Moreno, 2601.
P.D.; López-Valverde, V.; Steinseifer, J.; Fernando, T.M.; Moore, [109] Wang, H.; Li, F.; Du, C.; Wang, H.; Mahato, R.I.; Huang, Y. Dox-
H.M.; Fasching, P.A. Neoadjuvant palbociclib plus either giredes- orubicin and lapatinib combination nanomedicine for treating re-
trant or anastrozole in oestrogen receptor-positive, HER2-negative, sistant breast cancer. Mol. Pharm., 2014, 11(8), 2600-2611.
early breast cancer (coopERA Breast Cancer): an open-label, ran- http://dx.doi.org/10.1021/mp400687w PMID: 24405470
domised, controlled, phase 2 study. Lancet Oncol., 2023, 24(9), [110] Saloustros, E.; Mavroudis, D.; Georgoulias, V. Paclitaxel and
1029-1041. docetaxel in the treatment of breast cancer. Expert Opin. Pharma-
http://dx.doi.org/10.1016/S1470-2045(23)00268-1 PMID: cother., 2008, 9(15), 2603-2616.
37657462 http://dx.doi.org/10.1517/14656566.9.15.2603 PMID: 18803448
[97] Rice, S.; Amon, A.; Whitehead, S.A. Ethanolic extracts of black [111] Tarantino, P.; Morganti, S.; Uliano, J.; Giugliano, F.; Crimini, E.;
cohosh (Actaea racemosa) inhibit growth and oestradiol synthesis Curigliano, G. Margetuximab for the treatment of HER2-positive
from oestrone sulphate in breast cancer cells. Maturitas, 2007, metastatic breast cancer. Expert Opin. Biol. Ther., 2021, 21(2),
56(4), 359-367. 127-133.
http://dx.doi.org/10.1016/j.maturitas.2006.10.002 PMID: 17125943 http://dx.doi.org/10.1080/14712598.2021.1856812 PMID:
[98] Jain, S.; Spandana, G.; Agrawal, A.K.; Kushwah, V.; Thanki, K. 33238772
Enhanced Antitumor Efficacy and Reduced Toxicity of Docetaxel [112] Zhou, D.; Yu, X.; Song, Y.; Zeng, H.; Zhang, H.; Chen, B.; Wang,
Loaded Estradiol Functionalized Stealth Polymeric Nanoparticles. Y.; Li, H.; Liu, X.; He, Q.; Li, X.; Zhou, W. Screening of and
Mol. Pharm., 2015, 12(11), 3871-3884. mechanism underlying the action of serum- and glucocorticoid-
http://dx.doi.org/10.1021/acs.molpharmaceut.5b00281 PMID: regulated kinase 3-targeted drugs against estrogen receptor-positive
26375023 breast cancer. Eur. J. Pharmacol., 2022, 927, 174982.
[99] Flynn, C.R.; Kumar, A.P.; O’Shea, D.; Higgins, M.J. Alpelisib- http://dx.doi.org/10.1016/j.ejphar.2022.174982 PMID: 35569550
induced thyroiditis in a patient with metastatic breast cancer: Is [113] Schlam, I.; Moges, R.; Morganti, S.; Tolaney, S.M.; Tarantino, P.
routine monitoring of thyroid function required? Curr. Probl. Can- Next-generation antibody-drug conjugates for breast cancer: Mov-
cer Case Rep., 2023, 9, 100219. ing beyond HER2 and TROP2. Crit. Rev. Oncol. Hematol., 2023,
http://dx.doi.org/10.1016/j.cpccr.2023.100219 190, 104090.
[100] Biganzoli, L.; Cufer, T.; Bruning, P.; Coleman, R.; Duchateau, L.; http://dx.doi.org/10.1016/j.critrevonc.2023.104090 PMID:
Calvert, A.H.; Gamucci, T.; Twelves, C.; Fargeot, P.; Epelbaum, 37562695
R.; Lohrisch, C.; Piccart, M.J. Doxorubicin and paclitaxel versus [114] Shabani, H.; Karami, M.H.; Kolour, J.; Sayyahi, Z.; Parvin, M.A.;
doxorubicin and cyclophosphamide as first-line chemotherapy in Soghala, S.; Baghini, S.S.; Mardasi, M.; Chopani, A.; Moulavi, P.;
metastatic breast cancer: The European Organization for Research Farkhondeh, T.; Darroudi, M.; Kabiri, M.; Samarghandian, S. Anti-
and Treatment of Cancer 10961 Multicenter Phase III Trial. J. Clin. cancer activity of thymoquinone against breast cancer cells: Mech-
Oncol., 2002, 20(14), 3114-3121. anisms of action and delivery approaches. Biomed. Pharmacother.,
http://dx.doi.org/10.1200/JCO.2002.11.005 PMID: 12118025 2023, 165, 114972.
[101] Fuentes, N.; Silveyra, P. Estrogen receptor signaling mechanisms. http://dx.doi.org/10.1016/j.biopha.2023.114972 PMID: 37481931
Adv. Protein Chem. Struct. Biol., 2019, 116, 135-170. [115] Kamaruzman, N.I.; Aziz, N.A.; Poh, C.L.; Chowdhury, E.H. Onco-
http://dx.doi.org/10.1016/bs.apcsb.2019.01.001 PMID: 31036290 genic signaling in tumorigenesis and applications of siRNA nano-
[102] Dash, S.G.; Kantevari, S.; Guru, S.K.; Naik, P.K. Combination of therapeutics in breast cancer. Cancers (Basel), 2019, 11(5), 632.
docetaxel and newly synthesized 9-Br-trimethoxybenzyl-noscapine http://dx.doi.org/10.3390/cancers11050632 PMID: 31064156
improve tubulin binding and enhances antitumor activity in breast [116] Simpson, D.; Curran, M.P.; Perry, C.M.; Pritchard, K.I. Letrozole.
cancer cells. Comput. Biol. Med., 2021, 139, 104996. Drugs, 2004, 64(11), 1213-1230.
http://dx.doi.org/10.1016/j.compbiomed.2021.104996 PMID: http://dx.doi.org/10.2165/00003495-200464110-00005 PMID:
34753081 15161328
[103] Nagel, G.; Linseisen, J.; van Gils, C.H.; Peeters, P.H.; Boutron- [117] Bielawski, K.; Bielawska, A.; Muszyńska, A.; Popławska, B.;
Ruault, M.C.; Clavel-Chapelon, F.; Romieu, I.; Tjønneland, A.; Ol- Czarnomysy, R. Cytotoxic activity of G3 PAMAM-NH2 den-
sen, A.; Roswall, N.; Witt, P.M.; Overvad, K.; Rohrmann, S.; drimer-chlorambucil conjugate in human breast cancer cells. Envi-
Kaaks, R.; Drogan, D.; Boeing, H.; Trichopoulou, A.; Stratigakou, ron. Toxicol. Pharmacol., 2011, 32(3), 364-372.
V.; Zylis, D.; Engeset, D.; Lund, E.; Skeie, G.; Berrino, F.; Grioni, http://dx.doi.org/10.1016/j.etap.2011.08.002 PMID: 22004955
S.; Mattiello, A.; Masala, G.; Tumino, R.; Zanetti, R.; Ros, M.M.; [118] Harbeck, N.; Gnant, M. Breast cancer. Lancet, 2017, 389(10074),
Bueno-de-Mesquita, H.B.; Ardanaz, E.; Sánchez, M.J.; Huerta, 1134-1150.
J.M.; Amiano, P.; Rodríguez, L.; Manjer, J.; Wirfält, E.; Lenner, P.; http://dx.doi.org/10.1016/S0140-6736(16)31891-8 PMID:
Hallmans, G.; Spencer, E.A.; Key, T.J.; Bingham, S.; Khaw, K.T.; 27865536
Rinaldi, S.; Slimani, N.; Boffetta, P.; Gallo, V.; Norat, T.; Riboli, [119] Woods, B.; Veenstra, D.; Hawkins, N. Prioritizing pharmacogenet-
E. Dietary β-carotene, vitamin C and E intake and breast cancer ic research: a value of information analysis of CYP2D6 testing to
risk in the European Prospective Investigation into Cancer and Nu- guide breast cancer treatment. Value Health, 2011, 14(8), 989-
trition (EPIC). Breast Cancer Res. Treat., 2010, 119(3), 753-765. 1001.
http://dx.doi.org/10.1007/s10549-009-0444-8 PMID: 19565333 http://dx.doi.org/10.1016/j.jval.2011.05.048 PMID: 22152167
[104] You, L.; An, R.; Liang, K.; Wang, X. Send Orders of Reprints at [120] Bakker, G.H.; Setyono-Han, B.; Portengen, H.; De Jong, F.H.;
bspsaif@emirates.net.ae. Mini Rev. Med. Chem., 2013, 13, 101- Foekens, J.A.; Klijn, J.G.M. Treatment of breast cancer with differ-
105. ent antiprogestins: Preclinical and clinical studies. J. Steroid Bio-
http://dx.doi.org/10.2174/138955713804484785 PMID: 23020239 chem. Mol. Biol., 1990, 37(6), 789-794.
[105] Singh, S.K.; Singh, S.; Wlillard, J.; Singh, R. Drug delivery ap- http://dx.doi.org/10.1016/0960-0760(90)90421-G PMID: 2285592
proaches for breast cancer. Int. J. Nanomed., 2017, 12, 6205-6218. [121] Wani, K.; Tarawadi, K.; Kaul-Ghanekar, R. Nanocarriers for deliv-
http://dx.doi.org/10.2147/IJN.S140325 ery of herbal based drugs in breast cancer-an overview. J. Nano
[106] Ye, Y.; Huang, Z.; Zhang, M.; Li, J.; Zhang, Y.; Lou, C. Synergis- Res., 2015, 34, 29-40.
tic therapeutic potential of alpelisib in cancers (excluding breast http://dx.doi.org/10.4028/www.scientific.net/JNanoR.34.29
22 Anti-Cancer Agents in Medicinal Chemistry, XXXX, Vol. XX, No. XX Kashyap et al.

[122] Cao, J.; Wang, L.; Zhu, X.Z.; Liu, T.G.; Wang, J.Y. Chlorambucil [139] Cong, Y.; Zhang, S.Y.; Li, H.M.; Zhong, J.J.; Zhao, W.; Tang, Y.J.
combined with a fluorophore for targeted cancer therapy and real- A truncated DNA aptamer with high selectivity for estrogen recep-
time monitoring of cancer cell death. J. Mol. Struct., 2023, 1294, tor-positive breast cancer cells. Int. J. Biol. Macromol., 2023, 252,
136379. 126450.
http://dx.doi.org/10.1016/j.molstruc.2023.136379 http://dx.doi.org/10.1016/j.ijbiomac.2023.126450 PMID: 37634779
[123] Tamoxifen project clg. 2023. [140] Colditz, G.A.; Bohlke, K. Priorities for the primary prevention of
[124] Hu, F.; Wang Yi, B.; Zhang, W.; Liang, J.; Lin, C.; Li, D.; Wang, breast cancer. CA Cancer J. Clin., 2014, 64(3), 186-194.
F.; Pang, D.; Zhao, Y. Carotenoids and breast cancer risk: a meta- http://dx.doi.org/10.3322/caac.21225 PMID: 24647877
analysis and meta-regression. Breast Cancer Res. Treat., 2012, [141] Perez, E.A. Paclitaxel in Breast Cancer. Oncologist, 1998, 3(6),
131(1), 239-253. 373-389.
http://dx.doi.org/10.1007/s10549-011-1723-8 PMID: 21901390 http://dx.doi.org/10.1634/theoncologist.3-6-373 PMID: 10388129
[125] Ge, Y.; Domschke, C.; Stoiber, N.; Schott, S.; Heil, J.; Rom, J.; [142] Rouzier, R.; Perou, C.M.; Symmans, W.F.; Ibrahim, N.; Cristofan-
Blumenstein, M.; Thum, J.; Sohn, C.; Schneeweiss, A.; Beckhove, illi, M.; Anderson, K.; Hess, K.R.; Stec, J.; Ayers, M.; Wagner, P.;
P.; Schuetz, F. Metronomic cyclophosphamide treatment in metas- Morandi, P.; Fan, C.; Rabiul, I.; Ross, J.S.; Hortobagyi, G.N.;
tasized breast cancer patients: immunological effects and clinical Pusztai, L. Breast cancer molecular subtypes respond differently to
outcome. Cancer Immunol. Immunother., 2012, 61(3), 353-362. preoperative chemotherapy. Clin. Cancer Res., 2005, 11(16), 5678-
http://dx.doi.org/10.1007/s00262-011-1106-3 PMID: 21915801 5685.
[126] Martin, J.M.; Goldstein, L.J. Profile of abemaciclib and its poten- http://dx.doi.org/10.1158/1078-0432.CCR-04-2421 PMID:
tial in the treatment of breast cancer. In: OncoTargets and Therapy; 16115903
Dove Medical Press Ltd., 2018; Vol. 11, pp. 5253-5259. [143] Huntimer, E.D.; Halaweish, F.T.; Chase, C.C.L. Proliferative activ-
http://dx.doi.org/10.2147/OTT.S149245 ity of Echinacea angustifolia root extracts on cancer cells: Interfer-
[127] Lin, P.H.; Tseng, L.M.; Lee, Y.H.; Chen, S.T.; Yeh, D.C.; Dai, ence with doxorubicin cytotoxicity. Chem. Biodivers., 2006, 3(6),
M.S.; Liu, L.C.; Wang, M.Y.; Lo, C.; Chang, S.; Tan, K.T.; Chen, 695-703.
S.J.; Kuo, S.H.; Huang, C.S. Neoadjuvant afatinib with paclitaxel http://dx.doi.org/10.1002/cbdv.200690071 PMID: 17193302
for triple-negative breast cancer and the molecular characteristics in [144] Moya, E.; Lyons, B.Y.A.; Rcsi, F.F.R.; Edelstyn, D.G. “Smnallpox,
responders and non-responders. J. Formos. Med. Assoc., 2022, in Virus and Ricketisial Diseases of Man,” J. cliti. Path, 1962, 14,
121(12), 2538-2547. 855.
http://dx.doi.org/10.1016/j.jfma.2022.05.015 PMID: 35752529 [145] Kim, H.I.; Huang, H.; Cheepala, S.; Huang, S.; Chung, J. Curcumin
[128] Britt, K.L.; Cuzick, J.; Phillips, K.A. Key steps for effective breast inhibition of integrin (α6β4)-dependent breast cancer cell motility
cancer prevention. Nat. Rev. Cancer, 2020, 20(8), 417-436. and invasion. Cancer Prev. Res. (Phila.), 2008, 1(5), 385-391.
http://dx.doi.org/10.1038/s41568-020-0266-x PMID: 32528185 http://dx.doi.org/10.1158/1940-6207.CAPR-08-0087 PMID:
[129] Dwyer, P.J.O Phase I/pharmacokinetic reevaluation of thioTEPA. 19138983
Cancer Res., 1911, 51(12), 3171-3176. [146] Kaliyamoorthi, K.; Ramasamy, S.; Pillai, A.S.; Alexander, A.;
[130] Tarantino, P.; Hamilton, E.; Tolaney, S.M.; Cortes, J.; Morganti, Arivarasu, A.; Enoch, I.V.M.V. Camptothecin-loaded holmium fer-
S.; Ferraro, E.; Marra, A.; Viale, G.; Trapani, D.; Cardoso, F.; rite nanocarrier. Expanded activity on breast cancer cells. Mater.
Penault-Llorca, F.; Viale, G.; Andrè, F.; Curigliano, G. HER2-Low Lett., 2021, 285, 129164.
breast cancer: Pathological and clinical landscape. J. Clin. Oncol., http://dx.doi.org/10.1016/j.matlet.2020.129164
2020, 38(17), 1951-1962. [147] Woo, C.C.; Hsu, A.; Kumar, A.P.; Sethi, G.; Tan, K.H.B. Thymo-
http://dx.doi.org/10.1200/JCO.19.02488 PMID: 32330069 quinone inhibits tumor growth and induces apoptosis in a breast
[131] Sadegha, S.; Varshochian, R.; Dadras, P.; Hosseinzadeh, H.; cancer xenograft mouse model: the role of p38 MAPK and ROS.
Sakhtianchi, R.; Mirzaie, Z.H.; Shafiee, A.; Atyabi, F.; Dinarvand, PLoS One, 2013, 8(10), e75356.
R. Mesoporous silica coated SPIONs containing curcumin and si- http://dx.doi.org/10.1371/journal.pone.0075356 PMID: 24098377
lymarin intended for breast cancer therapy. Daru, 2022, 30(2), 331- [148] Susiriwatananont, T.; Poovorawan, N.; Teerapakpinyo, C.; Shuang-
341. shoti, S.; Jarutasnangkul, L.; Tumkosit, M.; Chattranukulchai, P.;
http://dx.doi.org/10.1007/s40199-022-00453-9 PMID: 36197594 Theerasuwipakorn, N.; Manasnayakorn, S.; Vinayanuwattikun, C.;
[132] Chen, L.; Nabil, A.; Fujisawa, N.; Oe, E.; Li, K.; Ebara, M. A Vorasettakarnkij, Y.; Sriuranpong, V. 259P Adjuvant doxorubicin-
facile, flexible, and multifunctional thermo-chemotherapy system cyclophosphamide in early-stage breast cancer provides long-term
for customized treatment of drug-resistant breast cancer. J. Control. cardiac safety. Ann. Oncol., 2023, 34, S286-S287.
Release, 2023, 363, 550-561. http://dx.doi.org/10.1016/j.annonc.2023.09.456
http://dx.doi.org/10.1016/j.jconrel.2023.10.010 PMID: 37804880 [149] Ershler, W.B. Capecitabine monotherapy: safe and effective treat-
[133] Sendur, M.A.N.; Zengin, N.; Aksoy, S.; Altundag, K. Everolimus: ment for metastatic breast cancer. Oncologist, 2006, 11(4), 325-
a new hope for patients with breast cancer. Curr. Med. Res. Opin., 335.
2014, 30(1), 75-87. http://dx.doi.org/10.1634/theoncologist.11-4-325 PMID: 16614228
http://dx.doi.org/10.1185/03007995.2013.846253 PMID: 24050600 [150] Baranauskaite, J.; Ockun, M.A.; Uner, B.; Gungor, B.; Duman, G.;
[134] Qin, S.Y.; Zhang, A.Q.; Cheng, S.X.; Rong, L.; Zhang, X.Z. Drug Tas, C.; Yesilada, E. Development and In vitro characterization of
self-delivery systems for cancer therapy. Biomaterials, 2017, 112, pullulan fast dissolving films loaded with Panax ginseng extract,
234-247. antioxidant properties and cytotoxic efficiency on lung and breast
http://dx.doi.org/10.1016/j.biomaterials.2016.10.016 PMID: cancer cell lines. J. Drug Deliv. Sci. Technol., 2022, 76, 103701.
27768976 http://dx.doi.org/10.1016/j.jddst.2022.103701
[135] Feldinger, K.; Kong, A. Profile of neratinib and its potential in the [151] Acconcia, F.; Fiocchetti, M.; Busonero, C.; Fernandez, V.S.; Mon-
treatment of breast cancer. In: Breast Cancer: Targets and Thera- talesi, E.; Cipolletti, M.; Pallottini, V.; Marino, M. The extra-
py; Dove Medical Press Ltd., 2015; Vol. 7, pp. 147-162. nuclear interactome of the estrogen receptors: implications for
http://dx.doi.org/10.2147/BCTT.S54414 physiological functions. Mol. Cell. Endocrinol., 2021, 538, 111452.
[136] Sverrisdottir, A.; Nystedt, M.; Johansson, H.; Fornander, T. Adju- http://dx.doi.org/10.1016/j.mce.2021.111452 PMID: 34500041
vant goserelin and ovarian preservation in chemotherapy treated [152] Chen, Y.; Chang, L.; Zhu, J.; Sun, W.; Wang, Y.; Li, W.; Liu, Y.;
patients with early breast cancer: results from a randomized trial. Yu, X.; Qin, J. Antimicrobial poly(aspartic acid) based self-healing
Breast Cancer Res. Treat., 2009, 117(3), 561-567. hydrogel with enhance cell migration rate for burn wound treat-
http://dx.doi.org/10.1007/s10549-009-0313-5 PMID: 19153828 ment. J. Drug Deliv. Sci. Technol., 2023, 89, 105062.
[137] Liu, X.; Hu, Q.; Wang, W.; Ma, H.; Pu, J.; Cui, J.; Gong, T.; Wu, http://dx.doi.org/10.1016/j.jddst.2023.105062
Y.; Lu, W.; Huang, J. A protein-fragment complementation assay [153] Lin, S.R. Natural compounds as potential adjuvants to cancer ther-
reveals that celastrol and gambogic acid suppress ERα mutants in apy: Preclinical evidence. Br. J. Pharmacol., 2019, 177(6), 1409-
breast cancer. Biochem. Pharmacol., 2021, 188, 114583. 1423.
http://dx.doi.org/10.1016/j.bcp.2021.114583 PMID: 33915156 [154] Zhang, X.; Spiegelman, D.; Baglietto, L.; Bernstein, L.; Boggs,
[138] Mustafa, Y.F. Chemotherapeutic applications of folate prodrugs: A D.A.; van den Brandt, P.A.; Buring, J.E.; Gapstur, S.M.; Giles,
review. Neuroquantology, 2021, 19(8), 99-112. G.G.; Giovannucci, E.; Goodman, G.; Hankinson, S.E.; Helzlsouer,
http://dx.doi.org/10.14704/nq.2021.19.8.NQ21120 K.J.; Horn-Ross, P.L.; Inoue, M.; Jung, S.; Khudyakov, P.; Lars-
Recent Prospectives of Cellular Signaling Role for Mammary Gland Anti-Cancer Agents in Medicinal Chemistry, XXXX, Vol. XX, No. XX 23

son, S.C.; Lof, M.; McCullough, M.L.; Miller, A.B.; Neuhouser, [168] Kremer, J.M. Toward a better understanding of methotrexate. Ar-
M.L.; Palmer, J.R.; Park, Y.; Robien, K.; Rohan, T.E.; Ross, J.A.; thritis Rheum., 2004, 50(5), 1370-1382.
Schouten, L.J.; Shikany, J.M.; Tsugane, S.; Visvanathan, K.; Wei- http://dx.doi.org/10.1002/art.20278 PMID: 15146406
derpass, E.; Wolk, A.; Willett, W.C.; Zhang, S.M.; Ziegler, R.G.; [169] Yosri, N.; Alsharif, S.M.; Xiao, J.; Musharraf, S.G.; Zhao, C.;
Smith-Warner, S.A. Carotenoid intakes and risk of breast cancer Saeed, A.; Gao, R.; Said, N.S.; Di Minno, A.; Daglia, M.; Guo, Z.;
defined by estrogen receptor and progesterone receptor status: a Khalifa, S.A.M.; El-Seedi, H.R. Arctium lappa (Burdock): Insights
pooled analysis of 18 prospective cohort studies. Am. J. Clin. Nutr., from ethnopharmacology potential, chemical constituents, clinical
2012, 95(3), 713-725. studies, pharmacological utility and nanomedicine. Biomed. Phar-
http://dx.doi.org/10.3945/ajcn.111.014415 PMID: 22277553 macother., 2023, 158, 114104.
[155] Shareef, M.; Ashraf, M.A.; Sarfraz, M. Natural cures for breast http://dx.doi.org/10.1016/j.biopha.2022.114104 PMID: 36516694
cancer treatment. Saudi Pharm J., 2016, 24(3), 233-240. [170] Mejía, J A.; Ollarves, J.C.; Zavaleta, L. Modulation of JAK-STAT
http://dx.doi.org/10.1016/j.jsps.2016.04.018 signaling by LNK: A forgotten oncogenic pathway in hormone re-
[156] Kolak, A.; Kamińska, M.; Sygit, K.; Budny, A.; Surdyka, D.; ceptor-positive breast cancer. Int. J. Mol. Sci., 2023, 24(19), 14777.
Kukiełka-Budny, B.; Burdan, F. Primary and secondary prevention http://dx.doi.org/10.3390/ijms241914777
of breast cancer. Ann. Agric. Environ. Med., 2017, 24(4), 549-553. [171] Buzdar, A.U.; Jonat, W.; Howell, A.; Plourde, P.V. ARIMIDEX: a
http://dx.doi.org/10.26444/aaem/75943 PMID: 29284222 potent and selective aromatase inhibitor for the treatment of ad-
[157] Odeh, F.; Ismail, S.I.; Abu-Dahab, R.; Mahmoud, I.S.; Al Bawab, vanced breast cancer. J. Steroid Biochem. Mol. Biol., 1997, 61(3-
A. Thymoquinone in liposomes: a study of loading efficiency and 6), 145-149.
biological activity towards breast cancer. Drug Deliv., 2012, 19(8), http://dx.doi.org/10.1016/S0960-0760(97)80006-4 PMID: 9365184
371-377. [172] Al-Radadi, N.S. Green Biosynthesis of Flaxseed Gold Nanoparti-
http://dx.doi.org/10.3109/10717544.2012.727500 PMID: 23043626 cles (Au-NPs) as Potent Anti-cancer Agent Against Breast Cancer
[158] Methotrexate increases extracellular adenosine release. 2023. Cells. J. Saudi Chem. Soc., 2021, 25(6), 101243.
[159] López-Tarruella, S.; Jerez, Y.; Márquez-Rodas, I.; Martín, M. http://dx.doi.org/10.1016/j.jscs.2021.101243
Neratinib (HKI-272) in the treatment of breast cancer. Future On- [173] Bkaily, G.; Jacques, D. Flaxseed as an Anticardiotoxicity Agent in
col., 2012, 8(6), 671-681. Breast Cancer Therapy. J. Nutr., 2020, 150(9), 2231-2232.
http://dx.doi.org/10.2217/fon.12.66 PMID: 22764764 http://dx.doi.org/10.1093/jn/nxaa213 PMID: 32725201
[160] Hong, H.; Chen, H.; Zhao, J.; Qin, L.; Li, H.; Huo, H.; Shi, S. [174] Taleat, Z.; Larsson, A.; Ewing, A.G. Anticancer Drug Tamoxifen
Bioinformatics analysis to identify breast cancer-related potential Affects Catecholamine Transmitter Release and Storage from Sin-
targets and candidate small molecule drugs. Mutat. Res., 2023, 827, gle Cells. ACS Chem. Neurosci., 2019, 10(4), 2060-2069.
111830. http://dx.doi.org/10.1021/acschemneuro.8b00714 PMID: 30763068
http://dx.doi.org/10.1016/j.mrfmmm.2023.111830 PMID: [175] Kort, A.; Sparidans, R.W.; Wagenaar, E.; Beijnen, J.H.; Schinkel,
37437506 A.H. Brain accumulation of the EML4-ALK inhibitor ceritinib is
[161] Jeong, Y.J. Rg3-enriched red ginseng extracts enhance apoptosis in restricted by P-glycoprotein (P-GP/ABCB1) and breast cancer re-
CoCl2-stimulated breast cancer cells by suppressing autophagy. J. sistance protein (BCRP/ABCG2). Pharmacol. Res., 2015, 102,
Ginseng Res., 2023, ••• 200-207.
http://dx.doi.org/10.1016/j.jgr.2023.06.001 PMID: 38223822 http://dx.doi.org/10.1016/j.phrs.2015.09.003 PMID: 26361725
[162] Hyoun, S.C.; Običan, S.G.; Scialli, A.R. Teratogen update: Metho- [176] Shrubsole, M.J.; Lu, W.; Chen, Z.; Shu, X.O.; Zheng, Y.; Dai, Q.;
trexate. Birth Defects Res. A Clin. Mol. Teratol., 2012, 94(4), 187- Cai, Q.; Gu, K.; Ruan, Z.X.; Gao, Y.T.; Zheng, W. Drinking green
207. tea modestly reduces breast cancer risk. J. Nutr., 2009, 139(2), 310-
http://dx.doi.org/10.1002/bdra.23003 PMID: 22434686 316.
[163] Sun, C.Y. Gilteritinib enhances anti-tumor efficacy of CDK4/6 http://dx.doi.org/10.3945/jn.108.098699 PMID: 19074205
inhibitor, abemaciclib in lung cancer cells. Front. Pharmacol., [177] Toy, W.; Shen, Y.; Won, H.; Green, B.; Sakr, R.A.; Will, M.; Li,
2023, 13, 829759. Z.; Gala, K.; Fanning, S.; King, T.A.; Hudis, C.; Chen, D.; Taran,
http://dx.doi.org/10.3389/fphar.2022.829759 T.; Hortobagyi, G.; Greene, G.; Berger, M.; Baselga, J.; Chandar-
[164] Jelinek, M.J.; Aggarwal, C. Adjuvant osimertinib: A new standard lapaty, S. ESR1 ligand-binding domain mutations in hormone-
of care. Oncologist., 2021, 26(4), 263-265. resistant breast cancer. Nat. Genet., 2013, 45(12), 1439-1445.
http://dx.doi.org/10.1002/onco.13634 http://dx.doi.org/10.1038/ng.2822 PMID: 24185512
[165] Honarvari, B.; Karimifard, S.; Akhtari, N.; Mehrarya, M.; [178] Rathore, C.; Rathbone, M.J.; Chellappan, D.K.; Tambuwala, M.M.;
Moghaddam, Z.S.; Ansari, M.J.; Jalil, A.T.; Matencio, A.; Trotta, Pinto, T.D.J.A.; Dureja, H.; Hemrajani, C.; Gupta, G.; Dua, K.;
F.; Yeganeh, F.E.; Farasati Far, B.; Arki, M.K.; Naimi-Jamal, Negi, P. Nanocarriers: More than tour de force for thymoquinone.
M.R.; Noorbazargan, H.; Lalami, Z.A.; Chiani, M. Folate-Targeted Expert Opin. Drug Deliv., 2020, 17(4), 479-494.
Curcumin-Loaded Niosomes for Site-Specific Delivery in Breast http://dx.doi.org/10.1080/17425247.2020.1730808 PMID:
Cancer Treatment: In Silico and In Vitro Study. Molecules, 2022, 32077770
27(14), 4634. [179] Coon, J.T.; Ernst, E. Panax ginseng. Drug Saf., 2002, 25(5), 323-
http://dx.doi.org/10.3390/molecules27144634 PMID: 35889513 344.
[166] Akrom, A.; Marstyawan, H.; Mustofa, M. P0051 Immunomodula- http://dx.doi.org/10.2165/00002018-200225050-00003 PMID:
tor effect of black cumin seed oil (BCO) in the inhibition of breast 12020172
cancer carcinogenesis in Dimenthylbenzantracene (DMBA)- [180] Benjamin, M.; Malakar, P.; Sinha, R.A.; Nasser, M.W.; Batra,
induced SD rats. Eur. J. Cancer, 2014, 50, e22. S.K.; Siddiqui, J.A.; Chakravarti, B. Molecular signaling network
http://dx.doi.org/10.1016/j.ejca.2014.03.095 and therapeutic developments in breast cancer brain metastasis.
[167] Malla, R.; Marni, R.; Chakraborty, A.; Kamal, M.A. Diallyl disul- Adv. Cancer Biol. Metastasis, 2023, 7, 100079.
fide and diallyl trisulfide in garlic as novel therapeutic agents to http://dx.doi.org/10.1016/j.adcanc.2022.100079 PMID: 36536947
overcome drug resistance in breast cancer. J. Pharm. Anal., 2022, [181] De, S.K. Medicines for Breast Cancer: Fundamentals of Cancer
12(2), 221-231. Detection, Treatment, and Prevention; Wiley, 2022, pp. 151-177.
http://dx.doi.org/10.1016/j.jpha.2021.11.004 PMID: 35582397 http://dx.doi.org/10.1002/9783527838561.ch6

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