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Table of Contents
REVIEW ARTICLE
Year : 2019  |  Volume : 6  |  Issue : 2  |  Page : 37-48

Size, site, and signaling: Three attributes of estrogen receptors


1 Primate Biology Laboratory, ICMR-National Institute of Research in Reproductive Health, Mumbai, Maharashtra, India
2 Structural Biology Laboratory, ICMR-National Institute of Research in Reproductive Health, Mumbai, Maharashtra, India

Date of Submission28-Sep-2019
Date of Decision15-Oct-2019
Date of Acceptance06-Nov-2019
Date of Web Publication22-Nov-2019

Correspondence Address:
Dr. Geetanjali Sachdeva
Primate Biology Laboratory, ICMR-National Institute of Research in Reproductive Health, Parel, Mumbai - 400 012, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/BMRJ.BMRJ_24_19

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  Abstract 


Estrogens are implicated in a diverse range of functions varying from reproduction, circulation, skeletal health to neuroprotection. Estrogens are also being increasingly recognized for their pathological contribution to cancers of various organs. This has spurred several investigations on estrogen-initiated signaling mechanisms in various cell types in physiological and pathological conditions. Estrogens exert their biological actions through a class of conventional nuclear receptors known as estrogen receptors (ERs), majorly of two subtypes – ERα and ERβ, both encoded by different genes, and each has multiple isoforms. It is reported that different ER subtypes and their specific isoforms have overlapping and nonoverlapping functions. Moreover, ER functions are highly cell-context specific. Thus, it is difficult to propose a unified scheme for estrogen signaling. Another layer of complexity is added by diverse subcellular localization, i.e., nucleus, plasma membrane, and cytosol, of ERs in estrogen-responsive tissues. Size as well as site dictates the sequence of cellular events triggered by estrogen signaling. This review compiles the existing information on different subtypes, different isoforms, and different sites of subcellular localization of ERs.

Keywords: Estrogen, estrogen receptors, isoforms, signaling, subtype


How to cite this article:
Desouza J, Gadkar S, Jagtap D, Sachdeva G. Size, site, and signaling: Three attributes of estrogen receptors. Biomed Res J 2019;6:37-48

How to cite this URL:
Desouza J, Gadkar S, Jagtap D, Sachdeva G. Size, site, and signaling: Three attributes of estrogen receptors. Biomed Res J [serial online] 2019 [cited 2019 Dec 16];6:37-48. Available from: http://www.brjnmims.org/text.asp?2019/6/2/37/271485




  Introduction Top


The human body is a complex enclosed system with multiple functions occurring simultaneously. Peptide, protein, and steroid hormones play critical roles in ensuring synchrony between different functions and physiological homeostasis. Like peptide and protein hormones, steroids act on a wide range of cells, tissues, and organs. Chemically steroids are lipophilic in nature and influence physiological processes such as growth, metabolism, sexual development, and differentiation through specific receptors.[1]

It was previously believed that steroids which are small molecules and products of metabolic pathways have not undergone molecular evolution. However, now, there exists evidence to demonstrate that metabolic pathways have also been modified during evolutionary descent and steroids have also evolved. Markov et al. demonstrated that in vertebrates, steroids are synthesized through side-chain cleavage and estrogen synthesis invariably involves aromatization, a more ancient estrogenic pathway.[2]

Estrogen synthesis initiates with side-chain cleavage of cholesterol to pregnenolone by the CYP11a enzyme and ends with aromatization of testosterone by CYP19A after a series of biochemical steps. However, pregnenolone synthesis from cholesterol is believed to be a vertebrate-specific phenomenon since CYP11a expression is restricted to vertebrates. Intriguingly, aromatization has been detected in mollusks and cnidarians which lack the CYP19A aromatase. To explain this, it was proposed that not only androgens but other steroids also undergo aromatization via a paralog CYP19 and form paraesterols. Paraesterols comprise of cholesterol side chain and its synthesis seems to be independent of the presence of progesterone, testosterone, or any side-chain intermediate. Thus, paraesterols appear to be the most primitive estrogen-like compound.[2]

Interestingly, mollusks which show aromatization despite lack of CYP19 display specific estrogenic actions, as revealed by estrogen binding to specific proteins or receptor-like sequences in their genome. The ancient steroid receptor discovered in mollusks was found to have 22 out of 26 sites in the ligand-binding pocket similar to that of estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). Sequence analysis of steroid receptors through the assessment of their evolutionary relationship has predicted ER to belong to the one clade and 3-ketosteroid receptor to the other clade. The 3-ketosteroid receptor further evolved to form progesterone receptor (PR), corticoid receptor, and androgen receptor. This diversification of steroid receptors resulted due to genome duplication and ligand exploitation.[3] Thus, the origin of estrogens and ERs date back to more than 500 million years ago in terms of evolutionary scale and this dyad of steroid-steroid receptor continues to be of extreme relevance in human physiology and pathology.

Estrogen, classically known as the female hormone, is synthesized mainly in the ovary in females and testes in males. Estrogens regulate multiple physiological functions by acting on gonads, brain, heart, liver, and bone. Estrogenic functions are not restricted to pubertal and adult lives but extend to embryonic development or life before birth.[4] Imbalance in the levels or functions of estrogens is associated with etiology of various cancers, metabolic diseases, and neurological diseases.[5] Estrogen-dependent cancers include cancers of reproductive organs, i.e., endometrium, breast, and ovary, wherein estrogens influence initiation, progression, and metastasis.[5],[6] Estrogens mediate their function through ER signaling, which activates expression of various oncogenes and cell cycle genes.[7] Conventional ERs act as transcription factors and there exist two major subtypes, i.e., ERα and ERβ. ERα is believed to execute oncogenic functions, whereas ERβ exerts protective functions.[8] However, both subtypes are known to have different isoforms and these isoforms exert regulatory functions by homo- or hetero-dimerization between themselves. It is very likely that the presence of more than one subtype and more than one isoform of each subtype allows precision in the regulation of estrogen signaling, inextricably linked with cell proliferation. Nonetheless, co-expression of more than one subtype and more than one isoform of each subtype renders the mechanism of estrogen signaling more intricate. This also makes therapeutic targeting of estrogen signaling extremely difficult.


  Estrogen Receptor Architecture and Signaling Top


Estrogens mediate its pleiotropic effects via two major classical receptors – ERα and ERβ. These receptors belong to type I class of nuclear receptors and on ligand binding act as transcription factors. Both the major classical ERs – ERα and ERβ – are evolutionarily conserved, coded by genes located on the chromosome 6 and 14, respectively, in humans. ERs have molecular structure of six domains encoded by eight exons namely A–F which differ in their functions. A/B domain codes for activation function 1 (AF1) which regulates transcription in a ligand-independent cell-specific manner.[9] The C domain encodes for DNA-binding domain (DBD). Within this domain exists a pair of C4-type zinc fingers which mediate binding of ERs to response elements called estrogen response elements (EREs) and coactivators. The first zinc finger within the DNA-binding monomer identifies the sequence 5'-AGGTCA-3' of the ERE duplex within the major groove while the second zinc finger is involved in the homodimerization of DBD [10] [Figure 1]b.[11],[12] Domain D comprises the hinge region that interconnects DBD and LBD and codes for the nuclear localization signal.[13] Domain E/F encodes for the ligand-binding domain (LBD), the heart of the structure, and AF2, which brings about transcription of downstream genes in ligand-dependent fashion.[14] The E domain structurally consists of 11 α-helices arranged in an antiparallel sandwich fold such that helices 4, 5, 6, 8, and 9 are surrounded on the one side by helices 1 and 3 while on the other side with helices 7, 10, and 11.[15] The conformation of the E domain does not differ much when compared in its ligand bound and unbound state, except for the structural orientation of the alpha 12 helix. Originally, the alpha 12 is oriented outward to make way for the ligand which on ligand-binding repositions itself to form a hydrophobic pocket exposing a coregulatory protein-binding surface [9],[10] [Figure 1]a and [Figure 1]c.[16],[17] Sequence alignment of both the receptors demonstrates a homology of 97% in their DBD, 60% in LBD, and 18% in the AF-2 domain.[18]
Figure 1: Three-dimensional structure depicting (a) ligand binding domain of estrogen receptor alpha bound to estradiol (blue color) (PDBID: 1A52[16]), (b) DNA-binding domain of estrogen receptor alpha (grey color depicts four zinc atoms) (PDBID: 1HCQ[12]), (c) Ligand-binding domain of estrogen receptor beta bound to estradiol (grey color) (PDBID: 3OLS[17]). The ribbon structure depicts different secondary structures based on the color code (β strand shown in yellow color; α helix in pink; β turn in blue; DNA in purple. Images were viewed in NGL, a 3D Viewer[11]

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For ERα, majorly, three isoforms [Figure 2] have been reported. The ERα66, the full-length receptor having molecular weight (M.W.) of 66 kDa, has been extensively studied. The other isoforms include ERα46 (M.W. 46 kDa) which lacks the first 173 amino acids mapping the AF1 domain and the ERα36 (M.W. 36 kDa) transcribed through an alternative transcription start site lacks a part of AF2 in addition to AF1 domain. ERα36 also has unique C terminal amino acid. Functionally, ERα46 represses ERα66 when co-expressed.[19] ERα36, on the other hand, inhibits signaling by ERα66 and ERβ, independent of its ligand status. To carry out transcriptional activities, ERα forms homodimers as well as heterodimers with ERβ. In tissues with higher expression of ERα, compared to ERβ, there occurs preferential homodimerization of ERα and heterodimerization of α/β than ERβ homodimerization.[20]
Figure 2: Diagrammatic representation of estrogen receptor alpha isoforms (Adapted from Jia et al., 2015)

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ERβ, on the other hand, has five major isoforms resulting from exon exclusion or skipping [Figure 3]. These isoforms are truncated in the F and E domains. ERβ1 (59 kDa), the full length and most studied ERβ, is fully functional and can induce transactivation on binding to the estrogen. ERβ2 (56 kDa) isoform has altered structure, with altered ligand-binding ability and also impaired ligand-induced transcriptional activity.[21] ERβ2 has been found to negatively regulate ERα.[22] Expression of ERβ3 is reported to be restricted to the testis.[23] ERβ4 (54 kDa) and ERβ5 (53 kDa) transcripts contain a part of exon 7 and different exon 8 sequence that creates 3D structures without 12α helix and F domain.[24] This leads to formation of an open conformation of the LBD pocket affecting the ligand-binding affinity.[25] Due to structural alterations, the ERβ2, ERβ4, and ERβ5 isoforms do not have transcriptional activity in their homodimer forms. However, these isoforms can heterodimerize with ERβ1. These heterodimers have higher transactivation activity than ERβ1 homodimers.[21]
Figure 3: Human estrogen receptor beta isoforms: Estrogen receptor beta 1 is the full length receptor while the other isoforms (β2-5) are generated through alternative splicing. These isoforms differ in the number of amino acids at the C- terminal (Adapted from Lipovka et al., 2016)

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ERs predominantly localize in the nucleus which on activation by estradiol (E2) or estrogen-like molecule initiate genomic signaling pathway. ERs undergo a conformational change on binding with E2 wherein they homo-or hetero-dimerize as ERα/ERβ and then translocate to the nucleus. In the nucleus, dimers bind to EREs, a 15 bp palindromic inverted repeats in or near the promoter regions, introns, or 3'untranslated regions of target genes, and recruit coregulators to initiate transcription. ERs can also regulate transcription of their target genes lacking ERE through their interaction with DNA-bound transcription factors such as SP1 or AP1.[26] ERs modulate transcriptional machinery by interacting with coactivators which in turn recruit chromatin remodeling complexes. This leads to modification of nucleosomal structures that enable recruitment of general transcription factors and other components of transcription machinery.[27] ER functions are also regulated by posttranslational modifications. Phosphorylation can modify the ability of ERα to bind to the DNA and thus affect transcription. In addition to genomic signaling, estrogenic effects are mediated through nongenomic signaling pathway by a pool of ERs present on the plasma membrane and other extranuclear sites, such as endoplasmic reticulum and mitochondria. The translocation of ERs on to the membrane occurs through posttranslational modifications, such as acylation, palmitoylation, and myristylation brought out by lipids.[28],[29] Activation of these membrane receptors by estrogen leads to interaction with factors such as Src, Ras, and Raf, resulting in rapid downstream effects which involve mobilization of intracellular calcium, stimulation of adenylate cyclase activity, cAMP production, as well as MAPK signaling pathway [30] [Figure 4].
Figure 4: Estrogen signaling pathway: 1: Estrogen receptor on ligand activation initiates transcription by binding to DNA. 2: Stimulating protein 1 is involved in indirect association of estrogen receptors to the DNA leading to transcription of genes. 3: Estrogen on binding to estrogen receptors on the membrane activates different downstream molecules through interaction with adaptor proteins such as Shc and SOS leading to modulation in cell growth and differentiation. 4: Membrane-initiated signal transduction pathways can influence genomic signaling through phosphorylation of estrogen receptors and coactivators

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  Physiological Roles of Estrogen Receptor Alpha and Estrogen Receptor Beta Top


Full-length ERα and ERβ are reported to be expressed in various tissues [Table 1]. ERα appears to be of predominance in uterus, pituitary glands, skeletal muscle, adipose tissue, and bone. In contrast, ERβ is known as the more predominant receptor in ovary, prostate, lung, central nervous system, and cardiovascular system.[31] Even within the same tissue, distribution of ER subtypes varies. For example, in the ovary, ERα is more abundant in theca cells and ERβ in the granulosa cells, while in the prostate, ERα is predominantly expressed in the stroma and ERβ in both cell compartments, i.e., stromal and epithelial cells.[32]
Table 1: Localization of estrogen receptor α and estrogen receptor β in different tissues under nonpathological conditions

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Differential expression of ERα and ERβ probably allows estrogenic effects to be tightly regulated in a spatial manner. Knockout studies in mice have demonstrated the role of ERα in the development of reproductive organs, such as uterus, mammary gland, and ovarian follicle maturation in females. In males, ERα is expressed in the prostate during embryonic development, and loss of ERα affects testes development and sperm production. Thus, ERα knockout (ERαKO) mice are infertile. In nonreproductive organs such as bone, ERα is positively associated with bone mineral density despite being expressed in low levels.[33] ERα also regulates glucose metabolism by modulating genes involved in gluconeogenesis, such as Pck-1 and G6Pase.[34] In endothelial cells, E2 activation of ERα is found to mediate remodeling of mesenteric arteries and in reendothelization.[35],[36] ERα is also expressed in neuronal cells as well as nonneuronal cells.[37],[38],[39] ERα in the hypothalamus is found to be expressed in the arcuate nucleus, the ventromedial nucleus of the hypothalamus, pro-opiomelanocortin, and SF1 neurons wherein it regulates energy homeostasis as they are the key centers for controlling food intake.[40],[41] This was further confirmed through hypothalamus-specific ERαKO mice model, which tends to develop metabolic syndrome.[42] ERα also regulates body weight through the neurons of the medial amygdala known as single-minded–1.[43]

ERβ in reproductive organs such as ovary has a role in preovulatory follicle maturation and ovulation.[44] In males, ERβ is expressed in prostate and testis but is not indispensable for fertility.[33],[45] In the brain, ERβ is expressed in the hypothalamus in paraventricular nucleus and regulates the hypothalamus–pituitary axis function in response to stress.[46] Furthermore, in the hippocampus, ERβ is found to mediate an antistress and antianxiety effect on stimulation with E2[72] and along with ERα exerts neuroprotective effects through upregulation of Bcl2 in the hippocampal neuron.[73]

Among immune cells, ERs are expressed in myeloid as well as lymphoid cells. On comparing the relative levels of the two ER subtypes, CD4 T-cells and macrophages showed higher levels of ERα while monocytes and B-cells predominantly express ERβ.[57],[74] Human primary monocytes have also been shown to express ERα46.[75] Activation of these receptors through estrogen stimulation regulates differentiation, maturation, and activation of the immune cells.[57] Stimulation of T-cells with increasing doses of estrogen has shown to influence the T-helper 1 response via ERα activation.[76] Estrogen stimulation of CD4+CD25- cells that are found to express ERα transform into regulatory T-cells.[77] ERα is reported to be involved in differentiation of dendritic cells from bone marrow cells.[78] ERα and ERβ also influence the release of pro-inflammatory cytokines such as tumor necrosis factor α and IL1β by monocytic cells via reduction in the expression of CD16.[79]


  Pathological Role of Estrogen Receptor Alpha and Estrogen Receptor Beta Top


Breast cancer

Breast cancer therapeutics is mainly directed to curb the estrogen action mediated through ERs. Based on the expression of ERs, breast tumors are classified as ERα-positive and ERα-negative tumors. The receptor status in breast tumors acts as a determinant for prognosis and choosing appropriate therapeutic options.[80]

In normal mammary glands and tumors, ERα66 is localized in the nuclei of epithelial cells that line the breast ducts and lobules.[55],[81] It is found to promote carcinogenesis by inhibiting apoptosis and regulating survival and multidrug resistance gene.[82] ERα function is also modulated through phosphorylation of its serine residues 118 and 167. Clinical studies have associated phosphorylation at these two potential sites with better prognosis and high survival rates.[83] In vitro attenuation of phosphorylation of ERα at these two sites in MCF7 breast cancer cell lines leads to increase in proliferation and metastasis potential and also alters expression of ERα target genes.[84] In addition to ERα66, ERα46 is expressed in breast tumors and a higher expression is observed in lower grades and smaller size tumors. ERα46 is known to abrogate the proliferative effects of ERα66. These two isoforms elicit different signaling through differential recruitment of cofactors and coactivators.[85] ERα36 is expressed in ER-positive and ER-negative cancer cell lines and localized in the cytoplasm and plasma membrane of breast tumors.[86],[87] The mechanism behind this translocation of ERα36 to the membrane is not known but has been assumed to involve potential posttranslational modifications of amino acids 25–30, 76–81, and 171–176 in the A/B domain by myristoylation. ERα36 membrane localization was found positively associated with patient survival in triple-negative breast cancer tumors.[88] However, another study reported association of ERα36 expression with poor prognosis in breast cancer patients.[81] In vitro experiments have shown ERα36 has procancerous effects in the presence of E2. This occurs via protein kinase C-induced ERK1/2 (MAPK) activation and PLD-LPAPI3K signaling, leading to proliferation, metastasis, and antiapoptosis. Activation of signaling cascade leads to increased expression of downstream genes such as SNAIL 1 and RankL and reduced expression of E-cadherin.[89],[90] In addition to this, ERα36-mediated nongenomic signaling occurs through EGFR/Src/shc complex. This implies that during estrogen signaling, ERα36 can dynamically change its interacting partners and involves crosstalk among multiple pathways.[86],[91]

ERα-30 is a novel splice variant of ERα identified in breast cancer tissue [Figure 2]. This variant lacks amino acids from the hinge region, the LBD and AF2 with an additional 10 unique amino acids at the C terminal end. This implies different transcriptional activities as compared to ERα-66. Further, expression levels of ERα-30 be associated with more aggressive type of correlate with absence of ERα66 and progesterone receptor in breast tumors. In MDA-MB-231 cell line, ERα30 overexpression led to higher migration, invasion, and proliferation. Although further investigations need to be carried out, the results demonstrate that ERα-30 could possibly act as a promising biomarker for metastasis and recurrence.[92]

Several other splice variants of ERα lacking certain regions of the exons such as Δ3, Δ4, Δ6, and Δ7 have been reported in certain breast cancer cell lines. However, their functional relevance is yet to be known.[93],[94] Wild-type ERα expression was found to be lower, while ERα variants with mutation in DBD were higher at transcript level in breast tumors compared to normal breast tissue.[95] Variants in breast tumors mostly included those containing 1, 2, or 3 exon deletions.[95] Thus, there exist multiple variants of ERα66, suggesting that the gene is under selective pressure during tumorigenesis. It will be of interest to investigate whether deletion, mutation and alternate splicing allow ER to exercise its function, irrespective of the presence of ligand, coactivators, and cofactors. On the other hand, it is also possible that such modifications relieve the ERs from some inhibitory influences.

ERβ is localized in the nuclei of ductal and luminal epithelial cells as well as stroma and myoepithelial cells of the breast tissue.[55] At the transcript level, ERβ receptor isoforms 1–5 are expressed in major breast cancer cell lines as well as primary breast cancer tissue.[96] At the protein level, till date, only ERβ1, ERβ2, and ERβ5 have been detected. These isoforms were found to be localized in the nuclei as well as cytoplasmic compartments.[97] The compartment-specific distribution pattern (cytosolic or nuclear) of the isoforms has been reported to correlate with overall survival (OS), disease-free survival (DFS), and treatment outcome. However, there is a lack of consensus with regard to isoform-specific outcome. Shaaban et al. reported no correlation of ERβ1 expression with OS while nuclear expression of ERβ2 was found correlated with better OS, DFS, and treatment response.[97] On the other hand, cytoplasmic ERβ2 (cERβ2) expression was found to correlate with poor outcomes and is often expressed in high-grade tumors and metastasis. In patients undergoing tamoxifen treatment, ERβ2 is associated with poor OS and DFS.[98] A positive correlation of ERβ1 with DFS and OS is reported in triple-negative breast cancer.[99] ERβ1 is proposed as a potential prognostic marker in patients treated with chemotherapy.[100]

ERβ seems to have a dual role in breast cancer cells. In MCF7 cells, ERβ induces antiproliferative effects and increases apoptosis via abrogation of ERα repression of p53. This activation of ERα repressed gene is under epigenetic regulation, wherein ERβ increases H3K4me3 mark, an indicator of gene activation.[101] However, in MDA-MB 231 cells, knockdown of ERβ leads to a gain in epithelial-like phenotype and decreased migration. The migratory potential of MDA-MB231 is regulated via interactions between ER/EGFR/IGF-IR pathways.[102]

ERα and ERβ have also been localized in the mitochondria in MCF-7 breast cancer cells, wherein they are reported to bind to the D loop of mitochondrial DNA that contains sequences which are homologous to EREs.[103] However, a direct or indirect role of ERs in regulating mitochondrial DNA transcription or transcription of nuclear-encoded mitochondrial respiratory complex genes remains to be deciphered.

Ovarian cancer

Clinical studies have not only correlated the expression levels of ERs with pathological grade but have also shown that differential compartmental expression of ERs can predict survival and aggressiveness of ovarian cancer.

ERα expression is found to increase from normal to benign and is highest in malignant cases while its loss is observed in clear cell carcinoma and mucinous carcinomas of the ovary.[104],[105] Further, Chan et al. have shown that the localization of cytoplasmic ERα (cERα); in different cellular compartments can predict disease progression, OS, and DFS.[106] Nuclear ERα (nERα) expression was found to be associated with more aggressive type of cancer while cERα may have a positive correlation with OS and DFS.[105] ERβ1, ERβ2, and ERβ5 isoforms were found to be differentially expressed in nuclear and cytoplasmic compartments of all different grades of ovarian cancer.[105],[107] In addition to these conventional isoforms, two other splice variants of ERβ generated by exon skipping were found to be expressed at the transcript level in normal ovary and ovarian cancer tissue. These two variants were first identified in MDA-MD-231 breast cancer cell lines. The proteins coded by these isoforms are expected to have different functions in comparison to the conventional forms since they lack AF1 and have deletions in the LBD and DBD.[108],[109]

nERβ1 expression is highest at transcript as well as protein level in normal ovarian tissue while it progressively decreases in high-grade, poorly differentiated, and metastatic foci regions.[106],[110],[111],[112],[113] In vitro ERβ overexpression is found to reduce proliferation and migration and to increase apoptosis.[109] Antiproliferative ability of ERβ was also evident in ovarian cancer cell lines such as OVCAR and OAW-42 treated with ERβ-specific agonists and ERβ siRNA.[114] ERβ1-mediated antiproliferative and antimetastatic effects involve p21, cyclin A2, fibulin 1c, and reduced phosphorylation of Akt, Rb as possible key mediators. ERβ can also repress action of ERα in ERα-positive BG1 cell line.[115]

Expression of ERβ2 and β5 has also been assessed in ovarian cancer tissues. nERβ5 is expressed in high levels in advanced carcinoma stages. Overexpression of ERβ5 in OVCA420 and ES-2 cell lines led to increased migration and invasion which was found to be mediated through FAK/Src activation.[105] ERβ2 is expressed in both the cellular compartments, and high-positive cytoplasmic reactivity has been linked with aggressive disease, chemoresistance, and decreased survival. The cause of this compartmental shift has been attributed to estrogen and could be demonstrated in ovarian cancer xenograft mice. These mice when ovarectomized express high levels of cERβ2 than their intact counterparts. This has led to speculations that the drop in the levels of estrogen during menopause can lead to the development of a more aggressive ovarian cancer phenotype through ERβ2 regulation.[107]

Prostate cancer

Clinical studies undertaken to understand the role of estrogens in prostate carcinogenesis have largely focused on the expression of ERs in different stages of disease progression such as prostatic epithelial neoplasia (PIN), high-grade PIN, and metastatic cancer. Although expression levels of ERs vary with stage and grade of disease, ERs are found to be localized in both nuclear and cytoplasmic compartments of prostate cells. When compared across different grades, ERα expression increases with increased severity of the disease.[116],[117],[118] ERαΔ5, a splice variant, has been reported in benign prostate hyperplasia (BPH) and tissue associated with tumor (TA). Its expression was found to be six times more in TA compared to BPH. ERαΔ5 variant lacks the LBD and has only 5% of the constitutive activity of the full-length receptor.[119] Another isoform ERα36 was also found to be present in the androgen-independent PC3 cells at transcript and protein levels. Activation of this receptor initiates rapid responses and involves ERK-1 phosphorylation.[120] In normal prostate tissues, wild-type ERβ (ERβ1) and its isoforms are reported to be expressed in basal as well as luminal epithelial cells.[52],[121] However, in prostate cancer (PCa) tissues, expression of ERβ1 is reduced whereas that of its isoform ERβ2 and β5 increases.[121] This implies that the expression of ERβ1 and its isoform is regulated by independent mechanisms. Zhang et al. demonstrated that the ERβ transcription is driven by two promoters 0K and 0N-upstream to 5'most-untranslated exons, preceding exon 1.[122],[123] Both promoters were found to be active in normal and cancerous prostate tissues. Promoter 0N with higher transcriptional activity has AP-2 site, whereas promoter 0K has CpG-rich region with lower transcriptional activity than that triggered by promoter 0N. Zhang et al. demonstrated preferential use of promoter 0N for ERβ1 transcription.[123] Lee et al. extended that these observations to demonstrate that ERβ1 and ERβ2 are transcribed from both promoters 0N and 0K whereas ERβ5 transcription is predominantly initiated from promoter 0K.[124] It was demonstrated that the transcripts transcribed from promoter 0K contain different combinations of untranslated exons 0Xs (0X1–8) which do not contribute to protein expression. Instead, the presence of 0Xs is known to inhibit protein translation through ribosome stalling, premature release of ribosome, and increased mRNA instability.[124],[125] It is likely that cis-regulating elements (modified due to epigenetic modification) and trans-acting factors eventually dictate the type of promoter usage. Nonetheless, these observations suggest that different isoforms of ERβ are generated not only by alternative splicing but also through posttranscriptional modifications.

Although most of the reports support the oncogenic role of ERα, contrasting inference has been reported in aggressive PCa cell line ARCaP which expresses low levels of ERα and androgen receptor. ERα ectopically expressed in ARCaP human prostate cells have shown to mediate antiproliferation via growth arrest in G1 cell cycle phase in E2-independent fashion.[126] ERβ1 acts as a tumor suppressor and multiple signaling cascades have been reported that help ERβ1 achieve its function. ERβ1-mediated apoptosis is induced by FOXO3a through downstream targeting of p53 upregulated modulator of apoptosis and activation of intrinsic apoptotic pathway by caspase 9.[127] ERβ1 is also found to have profound effects on epithelial–mesenchymal transition (EMT). PC3 cells treated with TGFβ or subjected to hypoxic microenvironment were found to be more invasive and migratory, and this was accompanied by a loss in ERβ1. ERβ1 loss leads to decrease or loss of E-cadherin promoter activity. The mechanism involved is ERβ1-mediated regulation of EMT through repression of VEGF (Vascular Endothelial Growth Factor)-A. VEGF-A also regulates localization of Snail-1 from the cytoplasm to the nucleus, a phenomenon observed in hypoxia. The repression of VEGF-A is mediated by ERβ1 which involves two different mechanisms. The first involves destabilization of HIF-1 (Hypoxia Inducible Factor) which regulates VEGF-A. The second is through repression of VEGF transcription via ERE.[128],[129] Ectopic expression of ERβ2 or 5 in PC3 cells led to an increase in their invasiveness whereas in vitro migration was found to be increased only in ERβ5-overexpressing PC3 cells.[121] Transcriptome analysis of PC3 cells transfected with a construct encoding ERβ1 showed a downregulation of cell-cycle regulating genes – C-myc and upregulation of Rb either at transcript or protein level. ERβ1 also negatively regulates RUNX2 and its downstream target SLUG. RUNX2 is an osseous master transcription factor that enhances metastatic ability of PC3 cells. Thus, ERβ1 may have a potential inhibitory role in PCa metastasis to the bone. ERβ2-expressing cells show higher expression of genes involved in proliferation, migration, and invasive behavior. In addition to this, ERβ2 was found to positively regulate MGAT5 which activates matriptase, known to influence the invasive potential of PCa cells.[130],[131] These results strongly support conclusions drawn by Leung et al., 2010,[121] supporting an antiproliferative role for ERβ1 and poor prognosis associated with higher expression of ERβ2.

Our group has been pursuing studies on detection and functional characterization of ERs on the plasma membrane of PCa cells. We demonstrated the presence of membrane-bound ERα and ERβ in normal as well as tumorigenic prostate epithelial cells.[132] Surface plasmon resonance experiments revealed binding of antibodies to conventional ERs to the plasma membrane extracts of LNCaP cells [Figure 5]a and [Figure 5]c and this binding was displaced by addition of E2 [Figure 5]b and [Figure 5]d. Interestingly, ERα showed remarkable co-localization with caveolin-1, an integral membrane protein and an important component of caveolae [Figure 6]. Thus, there exists a possibility of ERα protein transported from or to the plasma membrane via caveolae-derived vesicles in PCa cells. Further, estrogen binding to the plasma membrane of androgen-dependent as well as androgen-independent PCa cells was observed. Overall, these observations suggest the presence of both ERα and ERβ on the plasma membrane of PCa cells. However, it remains to be investigated whether plasma membrane localization of ERs is a constitutive process or a regulated event.
Figure 5: SPR analysis showing the real-time binding of cell surface protein fraction (CSP) of LNCaP cells containing estrogen receptors to immobilized polyclonal ERα and ERβ antibodies. Sensogram showing the binding of CSP (500ng-8μg), flowed over a surface of sensor chip immobilized with antibody specific against estrogen receptor alpha and estrogen receptor beta respectively (a and c). Sensograms showing the binding of CSP (1μg) to estrogen receptor alpha and estrogen receptor beta antibodies immobilized over a sensor chip in absence and presence of different concentrations of estradiol (1μM and 10μM) (b and d).

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Figure 6: Colocalization of caveolin-1 with estrogen receptor alpha in LNCaP cells. (a) caveolin-1 localization, (b) estrogen receptor alpha localization, (c) DAPI staining, (d) Merged picture showing colocalization of caveolin-1 with estrogen receptor alpha

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  Conclusion Top


ERs, a class of nuclear receptors, play crucial roles in various physiological functions. Their aberrant expression is not limited to cancer and extends to metabolic and aging-related diseases. It has emerged that while wild-type full-length transcripts of ERα and ERβ have contrasting functions, proteins encoded by the truncated forms of ERα and ERβ have functions, often opposing to the functions executed by the wild-type isoforms. Further, in clinical settings, the expression of ER isoforms in various tumor types is reported to be associated with survival and therapy outcomes. Presence of various isoforms explains variable effect of therapy seen in some patients. Detailed investigations need to be undertaken to elucidate the mechanisms by which different isoforms of ERα and ERβ are generated and transported to different subcellular compartments. In addition, it will be worthwhile to decode the functions of each isoform in different compartments. Furthermore, extensive efforts are required to test whether it is feasible to develop ER isoform-specific agonists and antagonists.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Cole TJ, Short KL, Hooper SB. The science of steroids. Semin Fetal Neonatal Med 2019;24:170-5.  Back to cited text no. 1
    
2.
Markov GV, Gutierrez-Mazariegos J, Pitrat D, Billas IML, Bonneton F, Moras D, et al. Origin of an ancient hormone/receptor couple revealed by resurrection of an ancestral estrogen. Sci Adv 2017;3:e1601778.  Back to cited text no. 2
    
3.
Thornton JW. Evolution of vertebrate steroid receptors from an ancestral estrogen receptor by ligand exploitation and serial genome expansions. Proc Natl Acad Sci U S A 2001;98:5671-6.  Back to cited text no. 3
    
4.
Bondesson M, Hao R, Lin CY, Williams C, Gustafsson JŠ. Estrogen receptor signaling during vertebrate development. Biochim Biophys Acta 2015;1849:142-51.  Back to cited text no. 4
    
5.
Deroo BJ, Korach KS. Estrogen receptors and human disease. J Clin Invest 2006;116:561-70.  Back to cited text no. 5
    
6.
Brown SB, Hankinson SE. Endogenous estrogens and the risk of breast, endometrial, and ovarian cancers. Steroids 2015;99:8-10.  Back to cited text no. 6
    
7.
Doisneau-Sixou SF, Sergio CM, Carroll JS, Hui R, Musgrove EA, Sutherland RL. Estrogen and antiestrogen regulation of cell cycle progression in breast cancer cells. Endocr Relat Cancer 2003;10:179-86.  Back to cited text no. 7
    
8.
Thomas C, Gustafsson JŠ. The different roles of ER subtypes in cancer biology and therapy. Nat Rev Cancer 2011;11:597-608.  Back to cited text no. 8
    
9.
Kampa M, Pelekanou V, Notas G, Stathopoulos EN, Castanas E. The estrogen receptor: Two or more molecules, multiple variants, diverse localizations, signaling and functions. Are we undergoing a paradigm-shift as regards their significance in breast cancer? Hormones (Athens) 2013;12:69-85.  Back to cited text no. 9
    
10.
Farooq A. Structural and functional diversity of estrogen receptor ligands. Curr Top Med Chem 2015;15:1372-84.  Back to cited text no. 10
    
11.
Rose AS, Bradley AR, Valasatava Y, Duarte JM, Prlic A, Rose PW. NGL viewer: Web-based molecular graphics for large complexes. Bioinformatics 2018;34:3755-8.  Back to cited text no. 11
    
12.
Schwabe JW, Chapman L, Finch JT, Rhodes D. The crystal structure of the estrogen receptor DNA-binding domain bound to DNA: how receptors discriminate between their response elements. Cell 1993;75:567-78.  Back to cited text no. 12
    
13.
Kumar R, Zakharov MN, Khan SH, Miki R, Jang H, Toraldo G, et al. The dynamic structure of the estrogen receptor. J Amino Acids 2011;2011:812540.  Back to cited text no. 13
    
14.
Hewitt SC, Korach KS. Estrogen receptors: Structure, mechanisms and function. Rev Endocr Metab Disord 2002;3:193-200.  Back to cited text no. 14
    
15.
Ruff M, Gangloff M, Wurtz JM, Moras D. Estrogen receptor transcription and transactivation: Structure-function relationship in DNA- and ligand-binding domains of estrogen receptors. Breast Cancer Res 2000;2:353-9.  Back to cited text no. 15
    
16.
Tanenbaum DM, Wang Y, Williams SP, Sigler PB. Crystallographic comparison of the estrogen and progesterone receptor's ligand binding domains. Proc Natl Acad Sci U S A 1998;95:5998-6003.  Back to cited text no. 16
    
17.
Möcklinghoff S, Rose R, Carraz M, Visser A, Ottmann C, Brunsveld L. Synthesis and crystal structure of a phosphorylated estrogen receptor ligand binding domain. Chembiochem 2010;11:2251-4.  Back to cited text no. 17
    
18.
Tremblay GB, Tremblay A, Copeland NG, Gilbert DJ, Jenkins NA, Labrie F, et al. Cloning, chromosomal localization, and functional analysis of the murine estrogen receptor beta. Mol Endocrinol 1997;11:353-65.  Back to cited text no. 18
    
19.
Flouriot G, Brand H, Denger S, Metivier R, Kos M, Reid G, et al. Identification of a new isoform of the human estrogen receptor-alpha (hER-alpha) that is encoded by distinct transcripts and that is able to repress hER-alpha activation function 1. EMBO J 2000;19:4688-700.  Back to cited text no. 19
    
20.
Cowley SM, Hoare S, Mosselman S, Parker MG. Estrogen receptors alpha and beta form heterodimers on DNA. J Biol Chem 1997;272:19858-62.  Back to cited text no. 20
    
21.
Leung YK, Mak P, Hassan S, Ho SM. Estrogen receptor (ER)-beta isoforms: A key to understanding ER-beta signaling. Proc Natl Acad Sci U S A 2006;103:13162-7.  Back to cited text no. 21
    
22.
Ogawa S, Inoue S, Watanabe T, Orimo A, Hosoi T, Ouchi Y, et al. Molecular cloning and characterization of human estrogen receptor betacx: A potential inhibitor ofestrogen action in human. Nucleic Acids Res 1998;26:3505-12.  Back to cited text no. 22
    
23.
Moore JT, McKee DD, Slentz-Kesler K, Moore LB, Jones SA, Horne EL, et al. Cloning and characterization of human estrogen receptor beta isoforms. Biochem Biophys Res Commun 1998;247:75-8.  Back to cited text no. 23
    
24.
Poola I, Abraham J, Baldwin K, Saunders A, Bhatnagar R. Estrogen receptors beta4 and beta5 are full length functionally distinct ERbeta isoforms: Cloning from human ovary and functional characterization. Endocrine 2005;27:227-38.  Back to cited text no. 24
    
25.
Kim CK, Torcaso A, Asimes A, Chung WC, Pak TR. Structural and functional characteristics of oestrogen receptor beta splice variants: Implications for the ageing brain. J Neuroendocrinol 2018;30:10.  Back to cited text no. 25
    
26.
Lipovka Y, Konhilas JP. The complex nature of oestrogen signalling in breast cancer: Enemy or ally? Biosci Rep 2016;36:e00352.  Back to cited text no. 26
    
27.
McKenna NJ, O'Malley BW. Combinatorial control of gene expression by nuclear receptors and coregulators. Cell 2002;108:465-74.  Back to cited text no. 27
    
28.
Acconcia F, Ascenzi P, Bocedi A, Spisni E, Tomasi V, Trentalance A, et al. Palmitoylation-dependent estrogen receptor alpha membrane localization: Regulation by 17beta-estradiol. Mol Biol Cell 2005;16:231-7.  Back to cited text no. 28
    
29.
Mundy DI. Protein palmitoylation in membrane trafficking. Biochem Soc Trans 1995;23:572-6.  Back to cited text no. 29
    
30.
Björnström L, Sjöberg M. Mechanisms of estrogen receptor signaling: Convergence of genomic and nongenomic actions on target genes. Mol Endocrinol 2005;19:833-42.  Back to cited text no. 30
    
31.
Dahlman-Wright K, Cavailles V, Fuqua SA, Jordan VC, Katzenellenbogen JA, Korach KS, et al. International union of pharmacology. LXIV. Estrogen receptors. Pharmacol Rev 2006;58:773-81.  Back to cited text no. 31
    
32.
Yaşar P, Ayaz G, User SD, Güpür G, Muyan M. Molecular mechanism of estrogen-estrogen receptor signaling. Reprod Med Biol 2017;16:4-20.  Back to cited text no. 32
    
33.
Lee HR, Kim TH, Choi KC. Functions and physiological roles of two types of estrogen receptors, ERalpha and ERbeta, identified by estrogen receptor knockout mouse. Lab Anim Res 2012;28:71-6.  Back to cited text no. 33
    
34.
Qiu S, Vazquez JT, Boulger E, Liu H, Xue P, Hussain MA, et al. Hepatic estrogen receptor α is critical for regulation of gluconeogenesis and lipid metabolism in males. Sci Rep 2017;7:1661.  Back to cited text no. 34
    
35.
Tarhouni K, Guihot AL, Freidja ML, Toutain B, Henrion B, Baufreton C, et al. Key role of estrogens and endothelial estrogen receptor alpha in blood flow-mediated remodeling of resistance arteries. Arterioscler Thromb Vasc Biol 2013;33:605-11.  Back to cited text no. 35
    
36.
Brouchet L, Krust A, Dupont S, Chambon P, Bayard F, Arnal JF. Estradiol accelerates reendothelialization in mouse carotid artery through estrogen receptor-alpha but not estrogen receptor-beta. Circulation 2001;103:423-8.  Back to cited text no. 36
    
37.
Villa A, Vegeto E, Poletti A, Maggi A. Estrogens, neuroinflammation, and neurodegeneration. Endocr Rev 2016;37:372-402.  Back to cited text no. 37
    
38.
Spary EJ, Maqbool A, Batten TF. Oestrogen receptors in the central nervous system and evidence for their role in the control of cardiovascular function. J Chem Neuroanat 2009;38:185-96.  Back to cited text no. 38
    
39.
Milner TA, Ayoola K, Drake CT, Herrick SP, Tabori NE, McEwen BS, et al. Ultrastructural localization of estrogen receptor beta immunoreactivity in the rat hippocampal formation. J Comp Neurol 2005;491:81-95.  Back to cited text no. 39
    
40.
Liu X, Shi H. Regulation of estrogen receptor alpha expression in the hypothalamus by sex steroids: Implication in the regulation of energy homeostasis. Int J Endocrinol 2015;2015:949085.  Back to cited text no. 40
    
41.
Xu Y, Nedungadi TP, Zhu L, Sobhani N, Irani BG, Davis KE, et al. Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction. Cell Metab 2011;14:453-65.  Back to cited text no. 41
    
42.
Musatov S, Chen W, Pfaff DW, Mobbs CV, Yang XJ, Clegg DJ, et al. Silencing of estrogen receptor alpha in the ventromedial nucleus of hypothalamus leads to metabolic syndrome. Proc Natl Acad Sci U S A 2007;104:2501-6.  Back to cited text no. 42
    
43.
Xu P, Cao X, He Y, Zhu L, Yang Y, Saito K, et al. Estrogen receptor-α in medial amygdala neurons regulates body weight. J Clin Invest 2015;125:2861-76.  Back to cited text no. 43
    
44.
Rumi MAK, Singh P, Roby KF, Zhao X, Iqbal K, Ratri A, et al. Defining the role of estrogen receptor β in the regulation of female fertility. Endocrinology 2017;158:2330-43.  Back to cited text no. 44
    
45.
Pettersson K, Gustafsson JA. Role of estrogen receptor beta in estrogen action. Annu Rev Physiol 2001;63:165-92.  Back to cited text no. 45
    
46.
Isgor C, Cecchi M, Kabbaj M, Akil H, Watson SJ. Estrogen receptor beta in the paraventricular nucleus of hypothalamus regulates the neuroendocrine response to stress and is regulated by corticosterone. Neuroscience 2003;121:837-45.  Back to cited text no. 46
    
47.
Denger S, Reid G, Kos M, Flouriot G, Parsch D, Brand H, et al. ERalpha gene expression in human primary osteoblasts: Evidence for the expression of two receptor proteins. Mol Endocrinol 2001;15:2064-77.  Back to cited text no. 47
    
48.
Pelletier G, El-Alfy M. Immunocytochemical localization of estrogen receptors alpha and beta in the human reproductive organs. J Clin Endocrinol Metab 2000;85:4835-40.  Back to cited text no. 48
    
49.
Horvath LG, Henshall SM, Lee CS, Head DR, Quinn DI, Makela S, et al. Frequent loss of estrogen receptor-beta expression in prostate cancer. Cancer Res 2001;61:5331-5.  Back to cited text no. 49
    
50.
Lazari MF, Lucas TF, Yasuhara F, Gomes GR, Siu ER, Royer C, et al. Estrogen receptors and function in the male reproductive system. Arq Bras Endocrinol Metabol 2009;53:923-33.  Back to cited text no. 50
    
51.
Iyer JK, Kalra M, Kaul A, Payton ME, Kaul R. Estrogen receptor expression in chronic hepatitis C and hepatocellular carcinoma pathogenesis. World J Gastroenterol 2017;23:6802-16.  Back to cited text no. 51
    
52.
Leav I, Lau KM, Adams JY, McNeal JE, Taplin ME, Wang J, et al. Comparative studies of the estrogen receptors beta and alpha and the androgen receptor in normal human prostate glands, dysplasia, and in primary and metastatic carcinoma. Am J Pathol 2001;159:79-92.  Back to cited text no. 52
    
53.
Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Proteomics. Tissue-based map of the human proteome. Science 2015;347:1260419.  Back to cited text no. 53
    
54.
Kovats S. Estrogen receptors regulate innate immune cells and signaling pathways. Cell Immunol 2015;294:63-9.  Back to cited text no. 54
    
55.
Speirs V, Skliris GP, Burdall SE, Carder PJ. Distinct expression patterns of ER alpha and ER beta in normal human mammary gland. J Clin Pathol 2002;55:371-4.  Back to cited text no. 55
    
56.
Saunders PT, Sharpe RM, Williams K, Macpherson S, Urquart H, Irvine DS, et al. Differential expression of oestrogen receptor alpha and beta proteins in the testes and male reproductive system of human and non-human primates. Mol Hum Reprod 2001;7:227-36.  Back to cited text no. 56
    
57.
Yakimchuk K, Jondal M, Okret S. Estrogen receptor α and β in the normal immune system and in lymphoid malignancies. Mol Cell Endocrinol 2013;375:121-9.  Back to cited text no. 57
    
58.
Cui J, Shen Y, Li R. Estrogen synthesis and signaling pathways during aging: From periphery to brain. Trends Mol Med 2013;19:197-209.  Back to cited text no. 58
    
59.
Lessey BA, Palomino WA, Apparao KB, Young SL, Lininger RA. Estrogen receptor-alpha (ER-alpha) and defects in uterine receptivity in women. Reprod Biol Endocrinol 2006;4 Suppl 1:S9.  Back to cited text no. 59
    
60.
Anamthathmakula P, Kyathanahalli C, Ingles J, Hassan SS, Condon JC, Jeyasuria P. Estrogen receptor alpha isoform ERdelta7 in myometrium modulates uterine quiescence during pregnancy. EBioMedicine 2019;39:520-30.  Back to cited text no. 60
    
61.
Wu JJ, Geimonen E, Andersen J. Increased expression of estrogen receptor beta in human uterine smooth muscle at term. Eur J Endocrinol 2000;142:92-9.  Back to cited text no. 61
    
62.
Hapangama DK, Kamal AM, Bulmer JN. Estrogen receptor β: The guardian of the endometrium. Hum Reprod Update 2015;21:174-93.  Back to cited text no. 62
    
63.
Zárate S, Seilicovich A. Estrogen receptors and signaling pathways in lactotropes and somatotropes. Neuroendocrinology 2010;92:215-23.  Back to cited text no. 63
    
64.
Taylor AH, Al-Azzawi F. Immunolocalisation of oestrogen receptor beta in human tissues. J Mol Endocrinol 2000;24:145-55.  Back to cited text no. 64
    
65.
Böttner M, Thelen P, Jarry H. Estrogen receptor beta: Tissue distribution and the still largely enigmatic physiological function. J Steroid Biochem Mol Biol 2014;139:245-51.  Back to cited text no. 65
    
66.
Zárate S, Jaita G, Ferraris J, Eijo G, Magri ML, Pisera D, et al. Estrogens induce expression of membrane-associated estrogen receptor α isoforms in lactotropes. PLoS One 2012;7:e41299.  Back to cited text no. 66
    
67.
Li L, Haynes MP, Bender JR. Plasma membrane localization and function of the estrogen receptor alpha variant (ER46) in human endothelial cells. Proc Natl Acad Sci U S A 2003;100:4807-12.  Back to cited text no. 67
    
68.
Xie H, Sun M, Liao XB, Yuan LQ, Sheng ZF, Meng JC, et al. Estrogen receptor α36 mediates a bone-sparing effect of 17β-estrodiol in postmenopausal women. J Bone Miner Res 2011;26:156-68.  Back to cited text no. 68
    
69.
Tuo B, Wen G, Wei J, Liu X, Wang X, Zhang Y, et al. Estrogen regulation of duodenal bicarbonate secretion and sex-specific protection of human duodenum. Gastroenterology 2011;141:854-63.  Back to cited text no. 69
    
70.
Yan Y, Yu L, Castro L, Dixon D. ERα36, a variant of estrogen receptor α, is predominantly localized in mitochondria of human uterine smooth muscle and leiomyoma cells. PLoS One 2017;12:e0186078.  Back to cited text no. 70
    
71.
Yang SH, Liu R, Perez EJ, Wen Y, Stevens SM Jr., Valencia T, et al. Mitochondrial localization of estrogen receptor beta. Proc Natl Acad Sci U S A 2004;101:4130-5.  Back to cited text no. 71
    
72.
Walf AA, Koonce CJ, Frye CA. Estradiol or diarylpropionitrile decrease anxiety-like behavior of wildtype, but not estrogen receptor beta knockout, mice. Behav Neurosci 2008;122:974-81.  Back to cited text no. 72
    
73.
Zhao L, Wu TW, Brinton RD. Estrogen receptor subtypes alpha and beta contribute to neuroprotection and increased Bcl-2 expression in primary hippocampal neurons. Brain Res 2004;1010:22-34.  Back to cited text no. 73
    
74.
Phiel KL, Henderson RA, Adelman SJ, Elloso MM. Differential estrogen receptor gene expression in human peripheral blood mononuclear cell populations. Immunol Lett 2005;97:107-13.  Back to cited text no. 74
    
75.
Murphy AJ, Guyre PM, Wira CR, Pioli PA. Estradiol regulates expression of estrogen receptor ERalpha46 in human macrophages. PLoS One 2009;4:e5539.  Back to cited text no. 75
    
76.
Cunningham M, Gilkeson G. Estrogen receptors in immunity and autoimmunity. Clin Rev Allergy Immunol 2011;40:66-73.  Back to cited text no. 76
    
77.
Tai P, Wang J, Jin H, Song X, Yan J, Kang Y, et al. Induction of regulatory T cells by physiological level estrogen. J Cell Physiol 2008;214:456-64.  Back to cited text no. 77
    
78.
Paharkova-Vatchkova V, Maldonado R, Kovats S. Estrogen preferentially promotes the differentiation of CD11c+CD11b (intermediate) dendritic cells from bone marrow precursors. J Immunol 2004;172:1426-36.  Back to cited text no. 78
    
79.
Kramer PR, Winger V, Kramer SF 17beta-estradiol utilizes the estrogen receptor to regulate CD16 expression in monocytes. Mol Cell Endocrinol 2007;279:16-25.  Back to cited text no. 79
    
80.
Dunnwald LK, Rossing MA, Li CI. Hormone receptor status, tumor characteristics, and prognosis: A prospective cohort of breast cancer patients. Breast Cancer Res 2007;9:R6.  Back to cited text no. 80
    
81.
Li L, Wang Q, Lv X, Sha L, Qin H, Wang L, et al. Expression and localization of estrogen receptor in human breast cancer and its clinical significance. Cell Biochem Biophys 2015;71:63-8.  Back to cited text no. 81
    
82.
Sayeed A, Konduri SD, Liu W, Bansal S, Li F, Das GM. Estrogen receptor alpha inhibits p53-mediated transcriptional repression: Implications for the regulation of apoptosis. Cancer Res 2007;67:7746-55.  Back to cited text no. 82
    
83.
Jiang J, Sarwar N, Peston D, Kulinskaya E, Shousha S, Coombes RC, et al. Phosphorylation of estrogen receptor-alpha at Ser167 is indicative of longer disease-free and overall survival in breast cancer patients. Clin Cancer Res 2007;13:5769-76.  Back to cited text no. 83
    
84.
Huderson BP, Duplessis TT, Williams CC, Seger HC, Marsden CG, Pouey KJ, et al. Stable inhibition of specific estrogen receptor α (ERα) phosphorylation confers increased growth, migration/invasion, and disruption of estradiol signaling in MCF-7 breast cancer cells. Endocrinology 2012;153:4144-59.  Back to cited text no. 84
    
85.
Chantalat E, Boudou F, Laurell H, Palierne G, Houtman R, Melchers D, et al. The AF-1-deficient estrogen receptor ERα46 isoform is frequently expressed in human breast tumors. Breast Cancer Res 2016;18:123.  Back to cited text no. 85
    
86.
Wang Z, Zhang X, Shen P, Loggie BW, Chang Y, Deuel TF. A variant of estrogen receptor-{alpha}, hER-{alpha} 36: Transduction of estrogen – And antiestrogen-dependent membrane-initiated mitogenic signaling. Proc Natl Acad Sci U S A 2006;103:9063-8.  Back to cited text no. 86
    
87.
Lee LM, Cao J, Deng H, Chen P, Gatalica Z, Wang ZY. ER-alpha36, a novel variant of ER-alpha, is expressed in ER-positive and – Negative human breast carcinomas. Anticancer Res 2008;28:479-83.  Back to cited text no. 87
    
88.
Pelekanou V, Notas G, Kampa M, Tsentelierou E, Radojicic J, Leclercq G, et al. ERα36, a new variant of the ERα is expressed in triple negative breast carcinomas and has a specific transcriptomic signature in breast cancer cell lines. Steroids 2012;77:928-34.  Back to cited text no. 88
    
89.
Chaudhri RA, Olivares-Navarrete R, Cuenca N, Hadadi A, Boyan BD, Schwartz Z. Membrane estrogen signaling enhances tumorigenesis and metastatic potential of breast cancer cells via estrogen receptor-α36 (ERα36). J Biol Chem 2012;287:7169-81.  Back to cited text no. 89
    
90.
Chaudhri RA, Hadadi A, Lobachev KS, Schwartz Z, Boyan BD. Estrogen receptor-alpha 36 mediates the anti-apoptotic effect of estradiol in triple negative breast cancer cells via a membrane-associated mechanism. Biochim Biophys Acta 2014;1843:2796-806.  Back to cited text no. 90
    
91.
Zhang XT, Kang LG, Ding L, Vranic S, Gatalica Z, Wang ZY. A positive feedback loop of ER-α36/EGFR promotes malignant growth of ER-negative breast cancer cells. Oncogene 2011;30:770-80.  Back to cited text no. 91
    
92.
Zhu H, Huang Y, Su H, Ma Y, Tao Y, Liao DJ, et al. Identification of a novel human estrogen receptor-alpha splice variant able to enhance malignant biological behaviors of breast cancer cells. Oncol Lett 2018;15:5339-44.  Back to cited text no. 92
    
93.
Al-Bader M, Ford C, Al-Ayadhy B, Francis I. Analysis of estrogen receptor isoforms and variants in breast cancer cell lines. Exp Ther Med 2011;2:537-44.  Back to cited text no. 93
    
94.
Pfeffer U, Fecarotta E, Castagnetta L, Vidali G. Estrogen receptor variant messenger RNA lacking exon 4 in estrogen-responsive human breast cancer cell lines. Cancer Res 1993;53:741-3.  Back to cited text no. 94
    
95.
van Dijk MA, Hart AA, van 't Veer LJ. Differences in estrogen receptor alpha variant messenger RNAs between normal human breast tissue and primary breast carcinomas. Cancer Res 2000;60:530-3.  Back to cited text no. 95
    
96.
Tong D, Schuster E, Seifert M, Czerwenka K, Leodolte S, Zeillinger R. Expression of estrogen receptor beta isoforms in human breast cancer tissues and cell lines. Breast Cancer Res Treat 2002;71:249-55.  Back to cited text no. 96
    
97.
Shaaban AM, Green AR, Karthik S, Alizadeh Y, Hughes TA, Harkins L, et al. Nuclear and cytoplasmic expression of ERbeta1, ERbeta2, and ERbeta5 identifies distinct prognostic outcome for breast cancer patients. Clin Cancer Res 2008;14:5228-35.  Back to cited text no. 97
    
98.
Baek JM, Chae BJ, Song BJ, Jung SS. The potential role of estrogen receptor beta2 in breast cancer. Int J Surg 2015;14:17-22.  Back to cited text no. 98
    
99.
Honma N, Horii R, Iwase T, Saji S, Younes M, Takubo K, et al. Clinical importance of estrogen receptor-beta evaluation in breast cancer patients treated with adjuvant tamoxifen therapy. J Clin Oncol 2008;26:3727-34.  Back to cited text no. 99
    
100.
Elebro K, Borgquist S, Rosendahl AH, Markkula A, Simonsson M, Jirstrom K, et al. High estrogen receptor beta expression is prognostic among adjuvant chemotherapy-treated patients-results from a population-based breast cancer cohort. Clin Cancer Res 2017;23:766-77.  Back to cited text no. 100
    
101.
Lu W, Katzenellenbogen BS. Estrogen receptor-beta modulation of the eralpha-p53 loop regulating gene expression, proliferation, and apoptosis in breast cancer. Horm Cancer 2017;8:230-42.  Back to cited text no. 101
    
102.
Piperigkou Z, Bouris P, Onisto M, Franchi M, Kletsas D, Theocharis AD, et al. Estrogen receptor beta modulates breast cancer cells functional properties, signaling and expression of matrix molecules. Matrix Biol 2016;56:4-23.  Back to cited text no. 102
    
103.
Chen JQ, Brown TR, Yager JD. Mechanisms of hormone carcinogenesis: Evolution of views, role of mitochondria. Adv Exp Med Biol 2008;630:1-8.  Back to cited text no. 103
    
104.
Sylvia MT, Kumar S, Dasari P. The expression of immunohistochemical markers estrogen receptor, progesterone receptor, Her-2-neu, p53 and Ki-67 in epithelial ovarian tumors and its correlation with clinicopathologic variables. Indian J Pathol Microbiol 2012;55:33-7.  Back to cited text no. 104
  [Full text]  
105.
Chan KK, Siu MK, Jiang YX, Wang JJ, Wang Y, Leung TH, et al. Differential expression of estrogen receptor subtypes and variants in ovarian cancer: Effects on cell invasion, proliferation and prognosis. BMC Cancer 2017;17:606.  Back to cited text no. 105
    
106.
Chan KK, Wei N, Liu SS, Xiao-Yun L, Cheung AN, Ngan HY. Estrogen receptor subtypes in ovarian cancer: A clinical correlation. Obstet Gynecol 2008;111:144-51.  Back to cited text no. 106
    
107.
Ciucci A, Zannoni GF, Travaglia D, Petrillo M, Scambia G, Gallo D. Prognostic significance of the estrogen receptor beta (ERbeta) isoforms ERbeta1, ERbeta2, and ERbeta5 in advanced serous ovarian cancer. Gynecol Oncol 2014;132:351-9.  Back to cited text no. 107
    
108.
Treeck O, Pfeiler G, Horn F, Federhofer B, Houlihan H, Vollmer A, et al. Novel estrogen receptor beta transcript variants identified in human breast cancer cells affect cell growth and apoptosis of COS-1 cells. Mol Cell Endocrinol 2007;264:50-60.  Back to cited text no. 108
    
109.
Treeck O, Pfeiler G, Mitter D, Lattrich C, Piendl G, Ortmann O. Estrogen receptor {beta} 1 exerts antitumoral effects on SK-OV-3 ovarian cancer cells. J Endocrinol 2007;193:421-33.  Back to cited text no. 109
    
110.
Rutherford T, Brown WD, Sapi E, Aschkenazi S, Muñoz A, Mor G. Absence of estrogen receptor-beta expression in metastatic ovarian cancer. Obstet Gynecol 2000;96:417-21.  Back to cited text no. 110
    
111.
Schuler-Toprak S, Weber F, Skrzypczak M, Ortmann O, Treeck O. Estrogen receptor beta is associated with expression of cancer associated genes and survival in ovarian cancer. BMC Cancer 2018;18:981.  Back to cited text no. 111
    
112.
Suzuki F, Akahira J, Miura I, Suzuki T, Ito K, Hayashi S, et al. Loss of estrogen receptor beta isoform expression and its correlation with aberrant DNA methylation of the 5'-untranslated region in human epithelial ovarian carcinoma. Cancer Sci 2008;99:2365-72.  Back to cited text no. 112
    
113.
De StefanoI, Zannoni GF, Prisco MG, Fagotti A, Tortorella L, Vizzielli G, et al. Cytoplasmic expression of estrogen receptor beta (ERβ) predicts poor clinical outcome in advanced serous ovarian cancer. Gynecol Oncol 2011;122:573-9.  Back to cited text no. 113
    
114.
Schüler-Toprak S, Moehle C, Skrzypczak M, Ortmann O, Treeck O. Effect of estrogen receptor β agonists on proliferation and gene expression of ovarian cancer cells. BMC Cancer 2017;17:319.  Back to cited text no. 114
    
115.
Bossard C, Busson M, Vindrieux D, Gaudin F, Machelon V, Brigitte M, et al. Potential role of estrogen receptor beta as a tumor suppressor of epithelial ovarian cancer. PLoS One 2012;7:e44787.  Back to cited text no. 115
    
116.
Pasquali D, Rossi V, Esposito D, Abbondanza C, Puca GA, Bellastella A, et al. Loss of estrogen receptor beta expression in malignant human prostate cells in primary cultures and in prostate cancer tissues. J Clin Endocrinol Metab 2001;86:2051-5.  Back to cited text no. 116
    
117.
Sehgal PD, Bauman TM, Nicholson TM, Vellky JE, Ricke EA, Tang W, et al. Tissue-specific quantification and localization of androgen and estrogen receptors in prostate cancer. Hum Pathol 2019;89:99-108.  Back to cited text no. 117
    
118.
Daniels G, Gellert LL, Melamed J, Hatcher D, Li Y, Wei J, et al. Decreased expression of stromal estrogen receptor alpha and beta in prostate cancer. Am J Transl Res 2014;6:140-6.  Back to cited text no. 118
    
119.
Taylor SE, Patel, II, Singh PB, Nicholson CM, Stringfellow HF, Gopala Krishna RK, et al. Elevated oestrogen receptor splice variant variant ERαΔ5 expression in tumour-adjacent hormone-responsive tissue. Int J Environ Res Public Health 2010;7:3871-89.  Back to cited text no. 119
    
120.
Pisolato R, Lombardi AP, Vicente CM, Lucas TF, Lazari MF, Porto CS. Expression and regulation of the estrogen receptors in PC-3 human prostate cancer cells. Steroids 2016;107:74-86.  Back to cited text no. 120
    
121.
Leung YK, Lam HM, Wu S, Song D, Levin L, Cheng L, et al. Estrogen receptor beta2 and beta5 are associated with poor prognosis in prostate cancer, and promote cancer cell migration and invasion. Endocr Relat Cancer 2010;17:675-89.  Back to cited text no. 121
    
122.
Zhao C, Lam EW, Sunters A, Enmark E, De Bella MT, Coombes RC, et al. Expression of estrogen receptor beta isoforms in normal breast epithelial cells and breast cancer: Regulation by methylation. Oncogene 2003;22:7600-6.  Back to cited text no. 122
    
123.
Zhang X, Leung YK, Ho SM. AP-2 regulates the transcription of estrogen receptor (ER)-beta by acting through a methylation hotspot of the 0N promoter in prostate cancer cells. Oncogene 2007;26:7346-54.  Back to cited text no. 123
    
124.
Lee MT, Ouyang B, Ho SM, Leung YK. Differential expression of estrogen receptor beta isoforms in prostate cancer through interplay between transcriptional and translational regulation. Mol Cell Endocrinol 2013;376:125-35.  Back to cited text no. 124
    
125.
Calvo SE, Pagliarini DJ, Mootha VK. Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans. Proc Natl Acad Sci U S A 2009;106:7507-12.  Back to cited text no. 125
    
126.
Ye Q, Cinar B, Edlund M, Chung LW, Zhau HE. Inhibition of growth and cell cycle arrest of ARCaP human prostate cancer cells by ectopic expression of ER-alpha. Mol Cell Biochem 2001;228:105-10.  Back to cited text no. 126
    
127.
Dey P, Ström A, Gustafsson JŠ. Estrogen receptor β upregulates FOXO3a and causes induction of apoptosis through PUMA in prostate cancer. Oncogene 2014;33:4213-25.  Back to cited text no. 127
    
128.
Wanami LS, Chen HY, Peiró S, García de Herreros A, Bachelder RE. Vascular endothelial growth factor-A stimulates snail expression in breast tumor cells: Implications for tumor progression. Exp Cell Res 2008;314:2448-53.  Back to cited text no. 128
    
129.
Mak P, Leav I, Pursell B, Bae D, Yang X, Taglienti CA, et al. ERbeta impedes prostate cancer EMT by destabilizing HIF-1alpha and inhibiting VEGF-mediated snail nuclear localization: Implications for gleason grading. Cancer Cell 2010;17:319-32.  Back to cited text no. 129
    
130.
Tsui KH, Chang PL, Feng TH, Chung LC, Sung HC, Juang HH. Evaluating the function of matriptase and N-acetylglucosaminyltransferase V in prostate cancer metastasis. Anticancer Res 2008;28:1993-9.  Back to cited text no. 130
    
131.
Dey P, Jonsson P, Hartman J, Williams C, Strom A, Gustafsson JA. Estrogen receptors beta1 and beta2 have opposing roles in regulating proliferation and bone metastasis genes in the prostate cancer cell line PC3. Mol Endocrinol 2012;26:1991-2003.  Back to cited text no. 131
    
132.
Gadkar S, Nair S, Patil S, Kalamani S, Bandivdekar A, Patel V, et al. Membrane-initiated estrogen signaling in prostate cancer: A route to epithelial-to-mesenchymal transition. Mol Carcinog 2019;58:2077-90.  Back to cited text no. 132
    


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Abstract
Introduction
Estrogen Recepto...
Physiological Ro...
Pathological Rol...
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Introduction
Estrogen Recepto...
Physiological Ro...
Pathological Rol...
Conclusion
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