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Mechanistic Insight of Drug Resistance with Special Focus on Iron in Estrogen Receptor Positive Breast Cancer

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Rashmi Mittal, Narender Chaudhry, Shubha Pathania and Tapan K. Mukherjee* Department of Biotechnology, Maharishi Markendeshwar University, Mullana, Haryana-133203, India

Abstract: Estrogens along with their receptors are required for the normal physiological development of women. However, in altered physiological conditions a high level of estrogens acts either as initiator or progressor of breast cancer. Approximately in 75% of estrogen dependent breast cancer cases estrogen receptors (ERs) are held responsible. Recent studies indicate that estrogens along with iron (Fe) concomitantly involved in the proliferation of ER+ breast cancer cells. While a number of antiestrogen/anti-ER drugs including selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs) and selective estrogen receptor down regulators (SERDs) are used to eradicate breast cancer but their action on Fe dependent breast cancer complication is not yet explored. Moreover, many of the ER+ breast cancer patients receiving anti-estrogen drugs relapsed within a couple of years and become resistant to antiestrogen therapy. Mutation and loss of affinity to the target molecule (ERs), loss or overexpression of ERs, along with activation of growth promoting pathways alternative to estrogen-ER pathways are the major reasons of drug resistance. Combinational therapy may be best alternative to antiestrogen relapsed patients. Some of the widely studied drug combinations are roscovitine (ROSC) and tamoxifen, metformin and tamoxifen, tamoxifen and RAD001. While in all these drug combinations anti-ER compound tamoxifen may be one of the major content, anti-Fe compounds are yet to be used as drug combination. The present review article describes all the currently studied drugs/drug combinations in ER+ breast cancer cells and future drug possibilities including anti-Fe compounds.

Keywords: Antiestrogens, breast cancer, combinational therapy, drug resistance, estrogens, estrogen receptors. INTRODUCTION

Estrogens are amongst the class of sex hormones that are synthesized from cholesterol and are secreted primarily by the ovaries, with secondary contributions by placenta, adipose tissue, testes, and adrenal glands. Estrogens are produced by both males and females, but the physiological levels of the hormone are significantly higher in females of reproductive age. These hormones are reported to be essential for the development and functioning of female primary and secondary reproductive organs including breast, uterus and ovary [1, 2].

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Physiological levels of estrogens are required for the proliferation of breast ductal epithelial cells [3]. Though estrogens are involved in epidemiologic processes in women but their higher levels cause carcinogenesis, by acting either as initiator (i.e., directly damaging DNA) or as promoter (i.e., promoting the growth and survival of initiated cells) [4, 5]. Elevated level of estrogens leads to various complications for e.g. breast cancer [6]. Breast cancer risk is predominant in women who either began menstruating at a young age (50% of cancers and is a matter of concern in our article [41]. If ER+ breast cancer is considered, interaction of ER with p53 may lead to the suppression

AKT-1 has been found to be in correlation with higher expression of erbB2 (also known as HER2/neu) in a panel of

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kinase (ILK) found active in many molecular pathways are implicated in cancer metastasis. Recent evidences suggest that ER extra nuclear signaling utilizes the ILK axis [76]. Thus, ILK inhibitors including QLT-0267 could be taken into consideration to restrain the motility of breast cancer cells [77]. Blocking of arginine methylases could be a possible therapeutic target as it is an established fact that, arginine methylation is also involved in extra-nuclear signaling of ERα. Compounds such as guanidine-nitrogen-substituted peptides or the thioglycolic amide RM65 may be useful to block this pathway [78, 79]. SRC3/AIB1 is frequently amplified or overexpressed in human breast cancer and is implicated in breast cancer progression in advanced ERα+ tumors. Mechanistic studies pin pointed that AIB1 overexpression activates the mTOR pathway and activation of this pathway is critical for AIB1-driven tumorigenesis [80]. Recent studies suggest that mTOR inhibition and ER targeted endocrine therapy may improve the outcome of the subset of patients with ER+ breast cancers overexpressing AIB1 [81]. Till now, we discussed the role of estrogens in complicating the disease. However, it is not just the estrogens responsible for the outcome, but its receptors too which make significance in causing and complicating the disease. So here onwards we will focus on the structure/ its types, physiologyand their role in causing the complication of disease under study.


breast cancer cell lines. Besides, AKT and mammalian target of rapamycin (mTOR) pathway is involved in breast ductal carcinoma development [60, 61]. P1(3)K pathway is also activated by ERs [62]. Phosphatase and tensin homologue (PTEN), a tumor suppressor protein is a critical counterregulator of P1(3)K [63] signaling and thus acts as one of the major tumor suppressors in breast cancer [64]. PTEN inhibits breast cancer through down-regulation of P1(3)K signaling which results in blockage of cell cycle progression [65]. ERα stimulates PI(3)K-AKT dependent cell survival in breast cancer by down regulating PTEN [64]. ERα binds to the regulatory subunit of P1(3)K (p85) in a ligand-dependent manner, thereby activating AKT [63]. Lata K et al. have also shown that in the in vitro cultured MCF-7 breast cancer cells 17α-EE causes AKT phosphorylation in a receptor dependent manner [11]. AKT signaling is actively involved in invasive ductal breast carcinoma and implicates ERα-mediated extra-nuclear actions leading to migration/invasion of tumor cells. Hence, we can conclude here that, phospho AKT (pAKT) status could be considered as a potential biomarker in the prediction of therapeutic responsiveness in invasive ductal breast carcinoma [66]. However, estrogens can also activate AKT phosphorylation in a receptor independent manner in ER- breast cancer cells and therefore more studies are needed to understand the exclusive role of ERs in estrogen dependent breast cancer complication [67].

Mittal et al.

1.4. Role of Iron in the Complication of Breast Cancer in Estrogen Receptor Positive Breast Cancer

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A long history of experimental and clinical literature reveals the importance of iron in enhancing the events of breast cancer outcome [68]. Estrogen along with Fe concomitantly found to be involved in proliferation of ER+ breast cancer [69]. Increased dietary intake of iron or administration of sub-cutaneous ferrous sulfate (FeSO4) is found to be involved in acceleration of breast cancer in female Sprague-Dawley rats [70, 71]. Breast tissues in postmenopausal women are locally exposed to high level of Fe and estrogens [69]. Fe is found to be an etiological factor in development of breast cancer in postmenopausal women. Combined exposure of Fe and estrogens enhances breast cell proliferation and shows the additive effect on growth of ER+ breast cancer MCF-7 cells [72]. Ferroportin is an iron efflux pump and hepacidin is a hormone which binds to ferroportin and triggers its degradation. Ferroportin and hepacidin are involved in mediating iron efflux in breast cancer growth and metastasis [73]. Miller observed that the reduced expression of ferroportin in breast cancer leads to accumulation of metabolically active iron which accelerates the carcinogenesis in breast cancer [74]. More studies are needed to understand the exact level of cross-talk between estrogen-ER dependent signaling pathways and iron activated pathways in breast cancer cells proliferation, survival and apoptosis. 1.5. Estrogen Mediated Production of Chemokines

ERα+ breast cancer cell’s metastasis has been found to be associated with chemokine signaling through stromal cell derive factor 1 (SDF-1) and C-X-C chemokine receptor type 4 (CXCR4). Therefore, CXCR4 signaling is considered as a rational therapeutic target for the treatment of ER+ advanced breast carcinomas [75]. Nodal molecules like integrin-linked

2. Role of Estrogen Receptors in the Complication of Breast Cancer To understand the complication caused by estrogen and ER in breast cancer, it is necessary here to understand its structure and its other physiological activities. Approximately 75% of breast tumors rely on estrogens. These tumors are generally referred to as "estrogen dependent". Tumors that do not rely on estrogens for growth are termed as "estrogen independent". Estrogen dependence can be predicted by the presence of ERs in tumor cells. ERs can be detected in breast tumor biopsy specimens using a technique which is popularly known as immunohistochemical staining. Tumor cells that express ERs are called as ER+ and are usually estrogen dependent. Tumors that lack ERs are called as ERand are usually estrogen independent [82, 83]. Two distinct ERs: Estrogen receptor alpha (ERα) and Estrogen receptor beta (ERβ) have been established in the humans. A third distinct type of ER termed as Estrogen receptor gamma (ERγ) was discovered in teleost fishes. Various ER isoforms may be generated because of mRNA splicing, out of which at least three isoforms of ERα and five of ERβ are known to be found in the human cells [84, 85]. With the advancement of research activities regarding these isoforms, their role in causation and complication of breast cancer became the point of interest for the cancer biology experts. The importance of specific ER subtypes was checked by gene knockout studies. These studies present a mechanistic insight about few questions like the consequences of ERα knockout in anti-ER treatment in breast cancer cells. Similarly ERα and ERβ combined knockout was carried out in mice models. These studies revealed several developmental facts. So here in this part of article we will deal with the involvement of the ER isoforms as developmental and physiological necessities of the body in relation to carcinogenesis as this event is considered to be a prominent hint for researchers.

Breast Cancer Drug Resistance

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ERα is predominantly involved in complication of breast cancer whereas ERβ plays the role in selected cases. Although ERα and ERβ are homologous structural receptors but exhibit different functions in vivo. Studies carried out on ERα and ERβ knockout mice reveal that ERα exhibits a dominant physiological effect in causing breast cancer [8688]. ERβ expression gradually decreases as normal breast cancer cells are transformed into the malignant type [89]. But despite the lower level ERβ expression, there exist a few studies which relate the phenomenon with tamoxifen resistance against the disease [90, 91] and to the perception of our article it may pose complication which may be overcome only by the combinational therapy.

Ying Chen in their experiments proved that ERβ overexpression in MCF-7 breast cancer cell line leads to elevation in IL-8 mRNA and protein levels [92]. An association of IL-8 and ERβ is found in both HER2 positive and negative tumors. Enhanced cell invasion, induced by HER2 overexpression is inhibited when the expression of IL-8 and ERβ is reduced. It is supposed that in the absence of ERα, ERβ in association with IL-8 may take over the role of major receptor hence causing progression of disease. To the best of our knowledge the events of carcinogenesis caused by ERβ in ERα knockout mice are still unknown. Fig. (1) illustrates the mechanism of binding estrogen to ERs thus causing the dimerization of receptor, nuclear localization of activated estrogen-ER complex, leading to transcription of estrogen responsive genes (Fig. 1). Complete structure of ERα and ERβ is now available to the researchers and it has revealed the locations of various domains over it. According to which, NH2 terminal consists of the A/B domains. But this article has point of interest in the C domain which forms the DNA-binding domain (DBD). Domains D/E/F constitutively forms the ligand-binding domain (LBD). AF-1 and AF-2 activation units are integral part of the DNA-binding and ligand-binding domains, respectively. ERα and ERβ, exhibit approximately 95% homology in the DNA-binding domain but differ in the ligand-binding domain with appearance of approximately 60% homology.

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Differences in the ligand-binding domain are responsible in part for ligand-specificity and the ratio of ERα and ERβ is a critical determinant of cellular response to endogenous estrogen and other ER agonists and antagonists [93-95]. ERα transactivation activity is mediated by the synergistic interaction of two domains designated AF-1 and AF-2. Physiologically AF-2 is responsible for the recruitment of co-activator and co-repressor proteins that allow ERα to swings between the roles of transcriptional activator and repressor. However, the mechanism responsible for AF-1 transcriptional activity remains a controversial suspense for the researchers [96]. Both receptors interact with the same conserved estrogen response element (ERE: 5'-GGTCAnnnTGACC-3') of the promoter/enhancer of estrogen responsive genes as either homo dimers (αα or ββ) or heterodimers (α-β) [97]. Estrogen binding alters the three-dimensional structure of ER to facilitate recruitment of co-activator complexes, thus leading to the activation of transcription of estrogen-inducible genes. The resultant transcriptional changes promote cell proliferation, survival, angiogenesis and tumor metastasis [12, 98].

Fig. (1). Showing binding of estrogen to estrogen receptors, causing the dimerization of estrogen receptors and thereafter nuclear localization of estrogen receptor complex takes place. Finally the complex binds to ERE causing transcription and hence translation. Abbreviation used: E= Estrogen, ER= Estrogen receptor, ERE= Estrogen response element, AF= Activation factor.

A number of observations reveal that, differential expression of distinct ER subtype mediates the pleiotropic and tissue specific effect of estrogens. ERα is the major ER subtype in the mammary epithelium and exclusively involved in breast cancer progression. Thus, a remarkable different expression pattern of ER, with higher ERα and lower ERβ levels are observed in malignant cells when compared to normal mammary epithelial or benign tumor cells [99]. 2.1. Role of Estrogen Receptor Alpha in the Complications Caused in Breast Cancer ERα transcriptional outcome is regulated by dynamic chromatin modifications of histone tails and the ligandbound ERα facilitates these modifications via co-regulator recruitment [100]. ERα co-regulator (AIB1) amplified in breast cancer promotes breast cancer metastasis by activation of Ets family of transcription factor (PEA3)-mediated matrix metalloproteinase 2 (MMP2) and MMP9 expression [101].


Steroid receptor coactivator-1 (SRC-1), another ER coregulator has also been shown to promote breast cancer invasiveness and metastasis by co-activating PEA3-mediated Twist express, a master regulator of metastasis [102].

work very efficiently in premenopausal women because the ovaries make too much aromatase. Therefore, they are used mainly in post-menopausal women, when hormonal level decreases due to menopause. Anti-hormone therapies using tamoxifen and anastrozole can be used to treat complex stages of breast cancer. It is a usual practice to treat women with early-stage breast cancer with surgery followed by antihormone therapy, radiation therapy, and if required then in some times chemotherapy. On the contrary women suffering from metastatic breast cancer but cannot be operated, are often given antihormone therapy, with or without chemotherapy. Risk of developing breast cancer can also be reduced if antihormone therapies are taken into consideration. Tamoxifen and another SERM i.e. raloxifene and several AIs have been found to reduce the risk of breast cancer among women at high risk for the disease [20]. Table. 1shows a tabulated presentation ofseveral drugs that target estrogen activity and have been approved by the FDA for the treatment of breast cancer and reduction of risk of breast cancer (Table 1).


Membrane-bound ERα has been reported to be associated with growth factor receptors such as IGF-1R, EGFR and HER2, such interactions play a role in cytoskeleton reorganization [103]. Dysregulation of HER2 in breast cancer cells enhances the expression of a metastasis associated protein 1 (MTA1s) isoform, which promotes the cytoplasmic sequestration of ERα leading to constitutive activation of mitogenactivated protein kinases (MAPKs) [104]. In case of breast cancer, some of the most important questions which need to be answered are whether it is of clinical value to measure ERβ along with ERα and whether ERβ can be a novel target in therapy.

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2.2. Role of Estrogen Receptor Beta in the Complication Caused in Breast Cancer

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In comparison to ERα the expression level of ERβ is relatively less in cancer cells [90, 91]. Exact association between ERβ and the complication of breast cancer is unclear. However, a number of studies observed a negative association between ERβ expression and breast cancer complication [105]. ERβ 1 is a full-length ligand binding isoform and is found to be antiproliferative and pro-apoptotic [99]. It has been shown that in in vitro cultured T47D cells, ERβ inhibits 17β-estradiol dependent proliferation of the cells [106]. Similarly, in an another recent study it has been shown that ERβ repress AKT dependent survival of breast cancer cells via down regulation of HER2/HER3 and upregulation of phosphatase and tensin homolog (PTEN), a tumor suppressor molecule [107]. In another observation it was shown that ERβ significantly reduces the transactivation of ERα in breast cancer cell lines [108]. However, another observation has shown that the loss of ERβ expression could be one of the events leading to the development of breast cancer [99]. More studies are needed to understand the exclusive role of ERβ in breast cancer complication. To proceed further it is worth mentioning here that, till now whatever we have discussed, makes a point of center in the subject matter. Hereafter we will deal with those therapeutic measures which are currently used but are proving inefficient regarding complete cure. 3. Endocrine Responsive Breast Cancer Therapy: Estrogen Receptors as Molecular Target of Breast Cancer Chemotherapy

Various drugs and their types are considered by the experts for cure. These drugs are classified into three different types of antihormone therapies which are used to treat women with ER+ breast tumors. These are SERMs, AIs and SERDs. SERMs, which include drugs such as tamoxifen, compete with estrogens for binding to the ERs. When tamoxifen binds to ER, estrogen becomes unable to bind with receptor, thus ultimately leading to disruption of estrogen signaling. AIs, which include drugs such as anastrozole, interfere with the body's ability to make estrogen. They do so by blocking the activity of aromatase which is an enzyme required in the final steps of estrogen production. AIs do not

Table 1.

Showing antiestrogen drugs with their generic and trade names.

Generic Name

Trade Name(s) Nolvadex®

Tamoxifen

Selective estrogen receptor modulators

Aromatase inhibitors

Selective Estrogen receptors downregulators

Soltamox®

Raloxifene

Evista®

Toremifene

Fareston®

Anastrozole

Arimidex®

Exemestane

Aromasin®

Letrozole

Femara®

Fulvestrant

Faslodex®

Many drugs, including tamoxifen, that inhibit ERs in the breast can actually activate ERs in other tissues. For example, tamoxifen can activate ERs in the bone and endometrium. This is why these agents are called "selective estrogen receptor modulators" or SERMs, rather than estrogen receptor inhibitors. The effects of 17β-estradiol and hormone-therapy on cell cycle progression are very well studied and analyzed showing that it is majorly the variations in ERα target gene expression which largely influence cell cycle regulators including cyclins. 3.1. Antiestrogen Drugs as Chemotherapeutic Agents Against Breast Cancer Antiestrogens antagonize the activity of estrogens and its receptor mediated biological effects. Various targeted drugs have been discovered for prevention and treatment of breast cancer. So here onwards in this part of article we will discuss various drug used as a chemotherapeutic agents against ER+ breast cancer.


3.1.1. Role of Tamoxifen in the Attenuation of Estrogen Dependent Breast Cancer

tamoxifen, ICI 182780 is a steroidal ER inhibitor and is often termed as a 'pure' antagonist exhibiting no estrogenic activity [121]. Fulvestrant exhibits anti-proliferative activity and leads to induction of apoptosis. They do not show crossresistance with tamoxifen, or ER agonist activity associated with tamoxifen. Fulvestrant is even found to be active in patients with breast cancer previously treated with a SERM such as tamoxifen, or with a non-steroidal AI such as anastrozole [122]. Fulvestrant competitively binds with ERs, with a binding affinity approximately 100 times greater than that of tamoxifen [123-126]. In animal models, this binding markedly attenuates the ability of the ERs to activate or inhibit gene transcription thus inhibiting its ability to induce breast cancer [127]. The binding of fulvestrant leads to impaired dimerization, increased ER turnover and disrupts nuclear localization [128]. Consequently, this induces a rapid degradation and loss of the ERs in breast carcinoma cells, making the receptor unavailable or unresponsive to estrogen or estrogen agonists.


Tamoxifen is considered as a non-steroidal anti-estrogen known to be the most widely used anti-estrogen for the treatment or prevention of ER+ breast cancer [109, 110]. Clinical trials reveal that the tamoxifen can be used as highly effective therapeutic agent in women suffering with various stages of breast cancer [111, 18]. For women with ER+ breast cancer, treatment for 5 years with adjuvant tamoxifen substantially reduces the chances of its recurrence [112]. Recent trials have revealed that continuing tamoxifen for 10 years rather than stopping at 5 years enhances the chances of further reduction in recurrence and mortality [113]. Many ER+ patients are diagnosed to be low reactive or resistant to tamoxifen [114] and such long treatment with tamoxifen causes serious side-effects such as increase in endometrial hyperplasia and carcinomas [115], vasomotor symptoms, gastrointestinal disturbance, atrophic vaginitis, changes in sexual functioning an excess of venothrombotic episodes and the development of de novo or acquired tamoxifen resistance [116, 117]. Hence, there is the need for a more effective therapy with fewer side-effects for these patients. Fig. (2) illustrates a schematic diagram showing the mechanism of action of tamoxifen to control estrogen-ER dependent gene regulation and attenuation of breast cancer complication (Fig. 2).


3.1.2. Role of Aromatase Inhibitors in the Attenuation of Estrogen Dependent Breast Cancer

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The aromatase inhibitors are superior to tamoxifen regarding both efficacy and toxicity and even have the potential to reduce ER- tumors. These drugs block the mechanism of production of estrogens from androgens. This is the main pathway of estrogen production in non-pregnant and more importantly in post-menopausal women [117, 118]. Estrogen production mediated by these tissues increases the local estrogen level and facilitates the pathogenesis of breast cancer. These drugs block the enzymes involved in estrogen biosynthesis (aromatase cytochrome P450 or estrogen synthetase) and thus inhibit the production of estrogen [119]. Aminogluthetimide was the first to be used from this group, but it is non-specific and can inhibit estrogen synthesis in many other tissues apart from the breast itself, with disastrous consequences. Second generation AIs exhibit higher potency and specificity which includes anastrozole, letrozole and exemestane. These have been tried in several clinical studies based on advanced breast cancer and promising results were awarded as a consequence of which it is now believed that they may replace popular SERMs like tamoxifen which are known to lose their potency with time [120]. 3.1.3. Role of Fulvestrant in the Attenuation of Estrogen Dependent Breast Cancer Till now in this part of the article we discussed about suppressors but as we need something to consider as a down regulator in order to enrich the article. So here in this section we are discussing fulvestrant, which is an ER antagonist indicated for the treatment of postmenopausal women with ER+, locally advanced or metastatic breast cancer. Unlike

Fig. (2). Showing competitive binding of tamoxifen to estrogen receptors occurs leading to nuclear localization of partially activated estrogen receptors complex, causing partial transcription and hence translation. Abbreviation used: T= Tamoxifen, ER= Estrogen receptor, ERE= Estrogen response element, AF= Activation factor.


4. Drug Resistance Against Anti-Estrogen Molecules in the Estrogen Receptor Positive Breast Cancer Drug resistance against antiestrogen chemotherapy is a very complex topic to study and difficult to analyze the facts affecting it. Hence it becomes needful here to divide this part of the article into several parts where each part deals with the issues causing resistance because of the focus point under consideration in that part.


Fulvestrant works in a dose dependent manner as indicated by the dose-related reduction of the ER index. Fulvestrant also consistently reduces progesterone receptor (PRs) levels in the tumor, in a dose-dependent manner [129]. Such a feature makes fulvestrant the first in a new class of antiestrogens and SERD without any agonist activity. Fig. (3) illustrates a schematic diagram showing the mechanism of action of fulvestrant to control estrogen-ER dependent gene regulation and attenuation of breast cancer complication (Fig. 3).

Mittal et al.

4.1. Drug Resistance Due to Persistence and Reoccurrence of Tumor Cells There is increasing evidence that tumor persistence and recurrence may be attributed to cancer stem cells (CSCs). CSCs model organize the heterogeneous tumors as hierarchies in which a sub-population of cancer cells i.e. tumorinitiating cells (TICs), possess stem cell-like properties. They can self-renew and simultaneously produce progenitors that rapidly proliferate and subsequently differentiate into diverse, more mature cell types that form the bulk of a tumor. Intrinsically TICs are resistant to conventional chemo and radiation therapies, and are capable of regenerating the cellular components of the original tumor eradicated by such treatments, finally leading to recurrence of the disease. Breast tumorspheres are developed from primary tumors and established cell lines. Breast cancer-derived sphere cells exhibit higher resistance to radiation and chemotherapy [130132]. Studies revealed that presence of ERα was not essential for tumorsphere formation or tumor growth, implying that TICs do not rely on ERα for self-renewal even though they may express detectable levels of ERα. It has been reported in a study that an association exists in myriad of cellular, molecular and biochemical alterations to the development of antiestrogen-resistant breast cancer [103]. 4.2. Drug Resistance in Breast Cancer due to Genetic Diversity and Mutation of the Estrogen Receptor Gene

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If complication of the disease is considered on the sole basis of genetic diversity and mutations, then it becomes needful here to divide this topic into parts dealing first with genetic diversity which includes splice variants/isoforms and then mutations. These are described as under:

Fig. (3). Showing attenuated dimerization takes place because of non-competitive binding of fulvestrant to estrogen receptors leading to reduced nuclear localization of fulvestrant and estrogen receptors complex and thus resulting in prevention of transcription, hence no translation. Abbreviation used: F= Fulvestrant, ER= Estrogen receptor, ERE= Estrogen response element, AF= Activation factor.

Though with the passage of time and advancement of research in the area of cancer biology, new drugs evolved but with them another problem was also encountered. It was drug resistance and this attracted the researchers to gain an understanding of it. This is important for us too, to discuss this aspect in next part as it will help us to understand the perception of our article.

4.2.1. Drug Resistance in Breast Cancer due to Presence of Isoforms of Estrogen Receptors Persistence of genetic diversity within breast cancer turns out to be more threatening than we originally believed. Estrogens are known to mediate its signaling pathway on binding with ER. Existence of several groups of ER splice variants is also found to be responsible for drug resistance in ER+ breast cancer. These splice variants exhibit either dominant positive or dominant negative effect and are also hypothesized to contribute to the hormone-independent phenotype of breast tumors. hERα−46 an isoform of ERα has been isolated from MCF-7 cell lines [133]. hERα-46 involved in mediating rapid estrogen signaling events like excess production of nitric oxide (NO) and activation of MAPK/ERK cell proliferation pathways [134, 135]. hERα-46 can also induce genomic activities in ERα breast cancer [135]. Thus,


the inhibition of ER by antiestrogens is not enough to overcome the complications of breast cancer, presence of various isoforms can lead to revival of estrogen mediated signaling pathway even in its absence too. 4.2.2. Drug Resistance in Breast Cancer due to Presence of Mutations in the Estrogen Receptor Gene Pool

4.4. Drug Resistance in Breast Cancer by the Action of Estrogen Receptor Related Receptor Gamma: an Orphan Nuclear Receptor One third of ER+ breast cancer treated with endocrine therapy fails to respond and remaining 70% are still at risk to relapse in future [144]. Although ER+ breast cancer cells are sensitive to growth inhibitory effects of antiestrogen but the existence of several histologic and molecular subtypes are responsible for drug resistance. SUM44/LCCTam cell lines isolated from invasive lobular metastasis shows the reduction in expression of ERα and a significant increase in expression of ERRgamma (ERRγ) on treatment with SERMs [144]. ERRγ is an orphan nuclear receptor without any known natural ligand [145, 146]. ERRγ and other nuclear receptors like ERRα1 and ERRα2 exhibit structural similarity to ER. Approximately 64% of DNA domain homology has been observed between ERRγ and ERα thus ERRγ can bind to EREs in similar manner to ERα [147]. ERRγ mRNA is found to be nearly 4 fold higher in ER+ breast cancer rather than epithelial mammary cells. Despite inhibiting the ER by using antiestrogen overexpression of ERR blocks the growth inhibitory effect of TAM and thus are found to be responsible for providing the resistance to breast cancer cells against SERMs. Experimental analysis in SUM44/LCCTam cell line reveals that ERRγ can be knocked out by siRNA and thus restores the sensitivity against antiestrogens [144]. Lata et al. also showed that treatment of MCF-7 breast cancer cells with 17α-EE induces the expression of ERRγ which in turn induces the proliferation of MCF-7 cells. Similarly ERRγ abrogates 17α-EE-dependent proliferation of MCF-7 cells [11].


A number of naturally occurring mutations have been identified in ER+ breast cancer. These mutations significantly reduces the growth inhibitory effect of antiestrogen either by altering the structure of ER so that drugs will not be able to effectively bind with them or by accelerating the growth factor receptors signaling pathways. Y537N (Tyr537Asn) mutation was discovered in a metastatic breast tumor [136]. This mutation found to be involved in elimination of carboxy-terminal tyrosine residue which is considered to be an important c-Src tyrosine phosphorylation site and thus alters the ligand binding, homodimerization and transactivation of ER. As a result of this, breast cancer drugs like ICI 164384 and tamoxifen do not effectively act on ER+ breast cancer cells. Another mutation at nucleotide 908 of ERα (A908G) has been identified in premalignant breast hyperplasia’s and invasive breast tumors from untreated patients [137, 138]. Molecular analysis of K303R ERα reveals that mutated arginine at the 303 position accelerates the phosphorylation of PKA [139] and AKT [140]. Enhanced growth factor receptor cross-talk with ER and alteration in ER structures leads to drug resistance in breast cancer [115]. Though events of resistance due to isoforms and mutations of ER gene in breast cancer are relatively low but complication caused poses a threat in cure of disease using monotherapeutic measures.


4.3. Drug Resistance in Breast Cancer due to Mutation of Breast Cancer Tumor Suppressor Gene 1

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Recently Kaplan et al. reported that most breast cancers carrying breast cancer 1 tumor suppressor gene (BRCA1) mutation were believed to be ER- with a basal like phenotype till it was discovered that up to one third of such cancers can be ER+ (2012) [141]. Authors in their study over the subject matter discovered besides the fact that ER+ sporadic cancers when compared to ER+ BRCA1 related cancers were significantly more often of invasive ductal type, of histologic grade 3 and had a higher mitotic rate with more frequent events but cluster analysis revealed that some ER+ BRCA1 cancers grouped more closely with sporadic ER+ cancers and had some similarities to ER- BRCA1-related cancers. Hence, the study enlightened a major point of focus for the treatment of the disease against the complication caused by mutation. As far as concern of menopause in women is considered, only 29% of the breast cancers that developed in pre-menopausal BRCA1 carriers are supposed to be ER+ whereas in case of post-menopausal women it is found to be 53% [142]. Research data fetched by the authors was found to be consistent with the reports published by Foulkes and colleagues who also found an increase in ER+ breast cancers with increasing age among BRCA1 mutation carriers [143].

Hence, we notice that there exist hurdles in the treatment of the disease because of the presence of substitute molecules such as ERRγ causing the activation of disease cascading pathway even in the presence of prescribed drugs like tamoxifen. And to our perception, such therapeutic measures should include combinational therapy. 4.5. Drug Resistance in Breast Cancer due to Over Expression of Human Epidermal Growth Factor Receptor-2 Endocrine therapy is a commonly and widely used systemic treatment in cases of breast cancer. However, there exists a challenge on account of treatment failure due to endocrine resistance in a significant proportion of patients [148]. ERα expression is a strong predictor of response to endocrine therapy and over expression or gene amplification of HER2 has been associated with more aggressive tumors and endocrine resistance [149]. HER2 can activate ERα via the PI(3)K-AKT signal transduction pathway and a molecular link has been defined between activation of this pathway and tamoxifen resistance [150]. Though AKT is supposed to be a target for the treatment of antiestrogen-resistant breast cancer cell lines hence antiestrogen-resistant breast cancer patients may benefit from treatment targeted to inhibit AKT signaling [151]. 4.6. Contribution of Activated Pro-survival and Proproliferative Signaling Pathway to Drug Resistance in Breast Cancer Activation of pro-survival and pro-proliferative signaling pathways also contributes to drug resistance. Approximately


5.1. Overcoming Drug Resistance in Breast Cancer Estrogen Receptor Positive Breast Cancer Cells To effectively block proliferation of antiestrogen-resistant breast cancer cells, it is necessary to identify a drug/ drug combination that can effectively block the ER mediated biological activities, tumor persistence, reoccurrence and overexpression of signaling pathways. The combinations being discussed are as following:


30% of breast cancer is caused due to the overexpression of HER2/neu gene (also called as c-erB2). HER2/neu gene is a protein tyrosine kinase transmembrane receptor [152, 153]. HER2/neu gene exhibits lesser sensitivity towards chemotherapy and radiotherapy. Nearly 50% of HER2+ patients are not sensitive even to trastuzumab (a HER2 inhibitor) treatment [154]. Valabrega et al. in their study reported an issue of resistance according to which most HER2+ patients encounter drug resistance to trastuzumab after one year of the treatment with trastuzumab [155]. HER2 + tumor expresses high-level of p-AKT [156]. PI(3)K-AKT signaling pathway acts as an important transducing signal pathway for retaining cell growth and proliferation and thus helps HER2+ breast cancer cells to maintain malignant biological characteristics [157, 158] and found to be the major mechanism leading to trastuzumab drug resistance [159, 160]. Experimental analysis reveals that LY294002 which is a PI(3)K inhibitor is capable of inhibiting its catalytic subunit i.e. p110 and blocks the PI(3)K-AKT signaling pathway,thereby inducing tumor cell apoptosis [161, 162]. LY294002 is also reported to inhibit the inactivity of trastuzumab drug against breast cancer cells [163].

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Acquired resistance of breast cancer cells to antiestrogens tamoxifen and fulvestrant is accompanied by the dysregulation of ERα-dependent signaling molecules such as coactivators as well as altered receptor-independent growth pathways including protein kinases [164, 151]. Few of the previously published reports, enlighten the fact that AKT protects breast cancer cells from antiestrogen induced apoptosis [150]. Receptor co-activator AIB1(amplified in breast cancer-1), usually found overexpressed in breast cancer, acts physiologically as an oncogene and transmits kinasemediating growth factor signaling to ERα [165]. 5. Possible Effective Solutions for Overcoming Drug Resistance in Breast Cancer: The Combinational Therapy

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Till now from our article we conclude that tamoxifen monotherapy failed apparently and caused resistance in the disease which led to the introduction of amromatse inhibitor in ER+ breast cancer but it also proved as a redundant measure. As a solution to this problem, fulvestrant was developed. But it has been mentioned above in the article that it is not just the receptor only which causes the progression and complication of disease but also there exists a number of other factors too such as mutations, presence of isoforms, P1(3)KAKT signaling pathway, accumulation of iron in postmenopausal women and inhibition of apoptosis. Hence, collectively these led to the escape of disease from monotherapy and caused drug resistance. It was now a need of researchers to concentrate on developing such measures which take care of all these points collectively. Here our article enlightens the way to combination therapy and to our perception we can say that the combination discussed hereafter by us may prove to be effective in overcoming such complicated resistance. This combinational therapy being considered in our article has a combination of drugs and inhibitors together which work in such a way that breast cancer may not find a way to escape from cure. Besides the combinational therapy we also suppose that therapeutic measures using some anti-iron compounds and flavonoids may also prove to be helpful to eradicate breast cancer.

5.1.1. Combination Therapy of Breast Cancer Using Roscovitine and Tamoxifen Targeting of cyclin-dependent kinases (CDKs) by CDKs inhibitors affects multiple cellular pathways in cancer cells thus inhibiting their persistence and proliferation. Synthetic CDK inhibitors are involved in regulating both cell cycle progression and transcriptional control. These are effective against both rapidly proliferating and quiescent cancer cells and can overcome multidrug resistance. Selective CDK inhibitor roscovitine (ROSC) arrests human ERα+ MCF-7 breast cancer cells in the G2-phase of the cell cycle [166] thereafter concomitantly induces caspase-3-independent apoptosis by inducing the pSer46-p53 tumor suppressor and transcriptional activation of the mitochondrial protein p53AIP1 [167]. 17β-estradiol induces phosphorylation of ERα at Ser118 but not at Ser104/Ser106 in MCF-7 cells. ROSC prevents this 17β-estradiol-promoted activated modification of ERα. In conjunction with tamoxifen, ROSC exhibits enhanced anti-proliferative activity and CDK inhibition in estrogendependent MCF-7 breast cancer cells, thus interaction between these two drugs was found to be strongly synergistic. ROSC negatively affects ERα, making it potentially useful in the treatment of estrogen-dependent breast cancer cells [168]. Figure 4 shown is a clear illustration of the event that ROSC acts as CDK inhibitor, hence inhibits the active CDKs ultimately resulting in prevention of replication (Fig. 4). 5.1.2. Combination Therapy of Breast Cancer Using Tamoxifen and RAD001 Degradation of AIB1 by RAD001, a derivative of the mTOR inhibitor rapamycin, has been reported to play a key role in breast tumor growth inhibition and the combination of RAD001 with tamoxifen was found to be more effective than tamoxifen monotherapy suggesting that degradation of AIB1 can contribute to the inhibition of breast cancer cell proliferation [81]. 5.1.3. TAS-108: A novel Steroidal Anti-estrogen for Treatment of Estrogen Receptor Positive Breast Cancer TAS-108 is a novel compound developed by SRI (Stanford Research Institute) and has completed its Phase I and Phase II clinical studies at multiple sites across the world. TAS-108 is found to be effective against tamoxifen and AIresistant breast cancers. It binds to ERα with high affinity, similar to 17β-estradiol and acts as ERα antagonist and partial ERα agonist. It also inhibits growth of tamoxifenresistant tumors, active against cell lines with reduced sensitivity to tamoxifen, fulvestrant, raloxifene and estrogenindependent lines.




Fig. (4). Showing partial activation of estrogen receptors take place because of binding of tamoxifen with estrogen receptors leading to nuclear localization of estrogen receptors and tamoxifen complex thus causing activation of CDKs. But ROSC inhibits activated CDKs, thus inhibiting the cell cycle and ultimately resulting in prevention of replication. Abbreviation used: T= Tamoxifen, ER= Estrogen receptor, ERE= Estrogen response element, AF= Activation factor, CDK= Cyclin dependent kinase, ROSC= Roscovitine.

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5.1.4. Combination therapy of breast cancer using metformin and tamoxifen

Metformin is a widely used anti-diabetic drug with excellent anti-cancer effects. It has been investigated that metformin has the additive effects with tamoxifen in ER+ breast cancer therapy. Metformin enhances tamoxifen mediated inhibition of proliferation, DNA replication activity and leads to induction of apoptosis in ER+ breast cancer cells. In addition, these tamoxifen-induced effects that were enhanced by metformin may be involved in the BAX-BCl2 apoptotic pathway and the AMPK-mTOR-p70S6 growth pathways. Finally here it can be concluded that, combination of these two drugs significantly inhibits tumor growth in vivo [169]. 6. Flavonoids as an Anticancer Agent to Overcome Drug Resistance in Breast Cancer There exists a number of flavonoids which are used as therapeutic measures in a number of diseases [170], we after

studying a number of research articles and reviews are now attracted to a flavonoid ‘apigenin’ which may prove extremely efficient in the cure of ER+ breast cancers. Hence this flavonoid makes a point of interest here in this article. Apigenin is commonly found in fruits and vegetables and is popularly known to restrain the growth of human tumor cell lines including breast cancer cells. Apigenin, is reported to exhibit dosage dependent response to the treatment of the breast cancer where at lower concentration it promotes the interaction of ERα with AIB1 thereby enhancing ERα transcriptional activity, hence resulting in overall growth stimulation. On the contrary, when this flavonoid is present at higher concentrations, it downregulates the level of AIB1 protein. These findings speculate that AIB1 is a potential target of apigenin and if this flavonoid is further explored for its role in overcoming the issue of drug resistance, apigenin may emerge as a new herbal drug of wonder [171-173].


7. Miraculous Role of Iron Chelators in Cancer Therapy

complication of breast cancer but also there exists a number of other factors too such as: mutations of the ERs, presence of ER isoforms, activation of ERRs, activation of proproliferative and prosurvival signaling pathways, accumulation of iron in post-menopausal women, and inhibition of apoptosis. Hence, collectively these led to the escape of disease from monotherapy and caused drug resistance. Researchers now need to concentrate on developing such measures which take care of all these points collectively and combinational therapy can be one amongst the possible and effective solutions. The drug combinations that may have the possibility of overcoming resistance are roscovitine + tamoxifen, tamoxifen + RAD001, TAS-108/metformin + tamoxifen/apigenin. Since none of the drug combinations used anti-Fe compound, it will be highly interesting to check the effect of anti-iron compounds as one of the constituents of combination therapy. It is a necessity of time to discover a combination of drug with an efficient iron chelator to overcome the complications caused in cure of disease even after the use of tamoxifen monotherapy.


In the area of cancer research, iron chelators are considered as anti-cancer agents majorly because of the fact that cancer cells require more of the iron as compared to normal cells due to increase in rate of metabolism. This fact attracted many researchers in order to use the chelators of iron in overcoming resistance. But few studies were focused on the use of iron chelators in the cure for breast cancer. One of such work was conducted by Jiang et al. in which it was shown that iron depletion environment was produced by the iron chelator “deferoxamine mesylate” or indium bound to transferrin in MCF-7 human breast cancer cell line, and this induced the characteristic features of apoptosis [174]. Similarly Pahl et al. in their study on a novel iron chelator, desferri-exochelin 772SM, found that at lower concentrations, this desferri-exochelin kills MCF-7 human breast cancer cells by the induction of apoptosis but on a strict note, it reversibly arrests the growth of normal human mammary epithelial cells without showing any cytotoxic features. Hence this study proved that this novel chelator exhibits cytotoxicity which is highly selective for cancer cells [175].

Mittal et al.

In another important study conducted by Rao et al. it was reported that lower concentration of Di-2-pyridylketone-4,4,dimethyl-3-thiosemicarbazone (Dp44mT) is selectively toxic to breast cancer cells as compared with normal breast epithelial cells. In this study it was investigated and revealed that if Dp44mT is present either as a lone agent or when present in combination with doxorubicin, kills breast cancer cells. Doxorubicin was reported to induce cytotoxicity and DNA damage. It was a very significant observation that cytotoxicity and DNA damage were both enhanced in the presence of low concentrations of Dp44mT [176].

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In several independent studies, it was revealed that targeting of HER2 by Trastuzumab (a monoclonal antibody) increases survival rates in early and metastatic breast cancer when given in combination with, or sequentially following, chemotherapy. Chemo-protective drugs, such as dexrazoxane which is an iron chelator, along with trastuzumab may prove effective in curing the disease effectively. Randomized phase III trial is under process to check effectiveness of this combination in the treatment of women suffering from stage IIIA, stage IIIB or stage IV breast cancer [177]. So here in this part of the article our hopes for overcoming drug resistance using iron chelators as a part of combination therapy are strengthened and we believe that if advanced studies are focused on this area, it will not be too far when a permanent and efficient cure for breast cancer will be discovered.

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest. ACKNOWLEDGEMENTS

We acknowledge the help provided by Maharishi Markendeshwar University, Mullana, Ambala, Haryana, India. REFERENCES [1]

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CONCLUSION & FUTURE PERSPECTIVE In conclusion, partial ER antagonist tamoxifen dependent monotherapy apparently failed and caused resistance in breast cancer which led to the introduction of aromatase inhibitor in ER+ breast cancer, but it also proved as a redundant measure. This further led to the development of fulvestrant, a pure ER antagonist. But inhibiting only the ERs is not an efficient solution to the problem of breast cancer and drug resistance associated with it, because it is not just the ERs only which are responsible for the progression and

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Received: May 21, 2014

Revised: July 30, 2014

Accepted: October 02, 2014