Endometrial carcinoma (EC) is a group of endometrial epithelial malignancies, most of which are adenocarcinomas and occur in perimenopausal and postmenopausal women. It is one of the most common carcinomas of the female reproductive system. It has been shown that the occurrence and development of EC is closely associated with the interaction between estrogen (estradiol, E2) and estrogen receptors (ERs), particularly ERα. As a key nuclear transcription factor, ERα is a carcinogenic factor in EC. Its interactions with upstream and downstream effectors and co-regulators have important implications for the proliferation, metastasis, invasion and inhibition of apoptosis of EC. In the present review, the structure of ERα and the regulation of ERα in multiple dimensions are described. In addition, the classical E2/ERα signaling pathway and the crosstalk between ERα and other EC regulators are elucidated, as well as the therapeutic targeting of ERα, which may provide a new direction for clinical applications of ERα in the future.
endometrial carcinomaestrogenestrogen receptor asignaling pathwayregulatorGeneral Program-Education Department of Zhejiang ProvinceY202249882Fundamental Research Funds for the Provincial Universities of Zhejiang, The Natural Science Foundation of Zhejiang ProvinceLY20C070001The National Natural Science Foundation of China31801165The K.C. Wong Magna Fund of Ningbo UniversityThis research was funded by the General Program-Education Department of Zhejiang Province (grant no. Y202249882), Fundamental Research Funds for the Provincial Universities of Zhejiang, The Natural Science Foundation of Zhejiang Province (grant no. LY20C070001), The National Natural Science Foundation of China (grant no. 31801165) and The K.C. Wong Magna Fund of Ningbo University.Introduction
Endometrial carcinoma (EC) is one of the most common gynecological malignancies and the sixth most common malignant disease worldwide. Its incidence is increasing year on year, and the age of onset is decreasing (1–3). The incidence of EC in developing countries (5.1/100,000 females) is lower than that in developed countries (13.8/100,000 females), but there is little difference in mortality rates between developed (2.63/100,000 females) and developing countries (1.52/100,000 females) (2,4). In addition, the incidence of EC is increasing in numerous developing countries (5). Data on the global burden of cancer in 2020, released by the International Agency for Research on Cancer, indicate that there were 417,000 new cases of EC and 97,000 deaths associated with EC in 2020 (2).
Based on its pathogenesis and biological behavior, EC can be divided into two types: Estrogen/17-β-estradiol (E2)-dependent EC (type I) and non-E2-dependent EC (type II) (3). The majority of type I ECs are endometrioid carcinomas, which are well differentiated, and a few are mucinous adenocarcinomas (6). Type II includes serous carcinoma and clear cell carcinoma (7). The majority of type II ECs do not express estrogen receptors (ERs) and may develop in a hormone-independent manner (7). The etiology of type I EC includes age, obesity, diabetes, hypertension, polycystic ovary syndrome, anovulation, infertility, nonpregnancy, early age at menarche, late age at menopause, ovarian neoplasms, use of exogenous estrogens and genetic factors (8,9). However, the main mechanism of its pathogenesis is that atypical hyperplasia of the endometrium occurs followed by carcinogenesis under the long-term stimulatory effect of E2 (10). For example, an early age at menarche, a late age at menopause and ovarian tumors all increase the cumulative exposure of the endometrium to E2, thereby increasing the risk of EC (11). In addition, tamoxifen, which is commonly used in the treatment of breast cancer, can act as an ER agonist and cause endometrial hyperplasia, polyps, cancer or sarcoma in the long term after surgery (12). Regarding type II, there is as yet no consensus on the etiology of precancerous lesions, but p53 mutations and the abnormal amplification of HER-2 are the main causes that are currently known (13). Therefore, from the classification criteria of EC, it may be noted that the occurrence and development of EC, particularly that of type I, are closely associated with E2.
E2 binds specifically with ERs to form a hormone-receptor complex, thus exerting its biological functions (14). There are two groups of ERs. One group includes the classical nuclear receptors ERα and ERβ, which are located in the nucleus and exert their functions by regulating the transcription of specific target genes (15). The other group comprises membranous receptors, including the membrane ER and G protein-coupled ER (GPER) family, which mainly play an indirect transcriptional regulatory function through the second messenger system, and in some cases appear to only have local effects in the brain (15,16). These two types of ER have a tissue/cell-specific distribution in the body and are involved in the regulation of various functions such as reproduction, learning, memory and cognition (15,17).
Of all ERs, ERα was the first to be identified, has been most comprehensively researched and is the most well understood (15). ERα is encoded by the ESR1 gene mapping to 6q25, and its main function is to stimulate and maintain the development of female reproductive organs and the emergence of secondary sexual characteristics (10,18,19). ERα exists not only in the reproductive tract and breast, but also in the liver, bone, cardiovascular system and brain (18,20). Combining immunohistochemistry with fluorescence in situ hybridization, Lebeau et al (21) detected the expression of ERα in 100% of 43 cases of endometrial hyperplasia, which is a precursor of EC, and 88.5% of 368 cases of EC. Although ERα is oncogenic in EC, patients with ERα-positive EC have an improved prognosis due to the rapid development of hormone therapy (22,23). In sporadic EC, it has been observed that the expression of ERα is strongly associated with a lower histological grade, and more effective response to hormone therapy in ~80% of EC cases (23). Notably, a search of The Cancer Genome Atlas (TCGA) database (https://portal.gdc.cancer.gov/genes/ENSG00000091831) reveals that ESR1 has the highest mutation frequency in EC, at 4.47%. Among these mutations, those of Y537 are the most numerous, suggesting that ESR1 Y537 mutation may be one of the driving factors for the occurrence and development of EC (Table I).
In the present review, the six domains of ERα and regulation of the ESR1 gene, ERα mRNA and ERα protein are firstly introduced, respectively. Next, the classical E2/ERα signaling pathway and the role of ERα in EC, according to upstream, co-regulatory and downstream factors, are described in detail. Finally, the clinical significance of ERα in EC is discussed, focusing on ERα-targeted therapy and its role as an indicator of good prognosis of EC.
Structure of ERα
ERα is a transcriptional factor composed of 595 amino acids and six different domains: A, B, C, D, E and F (Fig. 1) (24). The A domain (amino acids 1–37) and B domain (amino acids 38–180) constitute the ligand-independent activation function (AF)-1, which is independent of E2 activation (25). However, this functional region may regulate the transcription of E2-responsive genes by participating in the process of E2-ERα binding (25). In general, the primary function of AF-1 is the recruitment of co-regulatory proteins (26). The C domain (amino acids 181–263), which is also known as the DNA binding domain (DBD), contains a double zinc finger structure that contains four cysteines (27). The ERα homodimer binds to the palindromic GGTCA-nnn-TGACC sequence of target genes via the DBD to promote their transcription (28). Additionally, the binding of DBD and DNA is stabilized due to the action of the D domain (amino acids 264–302) (25). The D domain contributes to the recruitment of nuclear localization signal and co-regulatory proteins by coordinating the function of AF-1 and ligand-dependent AF-2 in ERα (29). Moreover, the D domain has been shown to acts as a hinge between the C domain and E domain (amino acids 303–546) (29). The E domain has several functions, such as binding to E2, receptor dimerization and binding to co-activators or co-inhibitors (28). In addition, the E domain constitutes the ligand-binding domain (LBD), containing AF-2 (28). When AF-2 encounters different types of estrogen, it adopts different conformations and determines which co-activators and/or co-suppressors are required for binding during the transcription of target genes (28). AF-1 and AF-2 coordinate with each other to maximize the transcriptional activity of ERα (25). The function of the F domain (amino acids 547–595) is relatively obscure. However, it has been reported that the F domain may be necessary for transcriptional activation and the functioning of anti-E2 drugs such as 4-hydroxytamoxifen (28,30).
ERβ is similar to ERα in protein structure, and also contains A, B, C, D, E and F domains (20). However, the major difference between ERβ and ERα is in AF-1. The activity of AF-1 of ERβ is relatively low, while that of AF-2 is similar to that of ERα, revealing that they have different effects on various E2-responsive genes at the transcriptional level (31,32). Specifically, when AF-1 and AF-2 are both required for gene transcription, the effect of ERβ is weaker than that of ERα, and they are equivalent if only AF-2 is required (32).
Regulation of ERα
The regulation of ERα can be divided into three different aspects: Transcription of ESR1, translation of ERα mRNA and post-translational modification of ERα protein (33–35). The different types of regulation of ERα can produce divergent effects, and sometimes even opposite results, particularly in the occurrence and development of EC (36,37). Given that the present review focuses on the roles of ERα in EC, the following sections mainly summarize the regulation of ERα in relation to EC (Table II).
Regulation of the transcription of ESR1
Compared with the translational regulation of ERα mRNA and the post-translational modification of ERα protein, the research into the transcriptional regulation of ESR1 is relatively unclear. However, by the analysis of ESR1 gene amplification and ERα protein expression in 368 EC tissue microarrays, Lebeau et al (21) found that the strong expression of ERα protein was significantly associated with ESR1 amplification in EC, suggesting that ESR1 amplification may be a mechanism by which ERα is overexpressed in EC, and could play an important role in the development of a significant proportion of EC cases. Kershah et al (38) found that the nuclear receptor co-regulators steroid receptor coactivator (SRC)-1, SRC-2, SRC-3, nuclear receptor corepressor and silencing mediator of retinoic acid and thyroid hormone receptor significantly increased mRNA expression in EC and were highly correlated with ERα mRNA, indicating that these regulatory factors may be associated with EC. Conversely, it has been suggested that ER-related receptor (ERR)α may regulate ERα-mediated pathways by interfering with ERα transcription (39). Also, in EC, methylation of the CpG island of the ESR1 gene has been found to be negatively associated with ERα expression (40). In addition, histone deacetylase (HDAC) inhibitors directly inhibit the transcription of ESR1 promoters and thus regulate the E2/ERα signaling pathway (33).
Regulation of the translation of ERα mRNA
Studies on translational regulation have mainly focused on the regulation of ERα mRNA by microRNAs (miRNAs or miRs). Bao et al (36) showed that miR-107-5p directly targets ERα mRNA to downregulate the expression of ERα mRNA and protein, thereby promoting tumor proliferation and EC invasion. Similarly, other studies have shown that miR-222-3p downregulates the expression of ERα, thereby promoting the proliferation and invasion of EC and increasing raloxifene resistance (41,42). Furthermore, miR-206 has been reported to inhibit ERα-dependent proliferation, impair the invasion ability of ERα-positive EC cells, and induce cell cycle arrest, indicating that abnormal miR-206 expression may be associated with the occurrence of EC (34). In addition to miRNA, a study by Zhang et al (43) confirmed that the stimulation of peroxisome proliferator-activated receptor γ (PPARγ) expression inhibited ERα expression at the mRNA and protein levels, and impaired the ability of Ishikawa cells to migrate and invade. Therefore, activation of PPARγ may enhance the effects of anti-E2 therapy in ERα-positive EC through ERα-mediated ER transactivation (43).
Regulation of the post-translational modification of ERα protein
The post-translational modification of ERα includes phosphorylation, ubiquitination, acetylation, sumoylation, methylation and glycosylation, among which phosphorylation, ubiquitination and acetylation are associated with EC development (37,44–48). Phosphorylation of ERα generally regulates the transcriptional activity of ERα by regulating the interaction between the AF domain and transcription co-activators (Fig. 1) (49). Kato et al (50) showed that MAPK-mediated phosphorylation of ERα S118 is necessary for the activity of AF-1, in vivo and in vitro. Furthermore, another study demonstrated that the phosphorylation of ERα S118 mediated by MAPK signaling pathway promotes uterine leiomyoma cell growth (35). Vilgelm et al (51) found that the deletion of Pten activates AKT in mouse endometrium, which leads to an increase in the phosphorylation of ERα S167, thereby increasing the ability of ERα to activate the transcription of several target genes. Similarly, Kato et al (52) found that the mTOR/p70 S6 kinase 1 and MAPK/p90 ribosomal S6 kinase signaling pathways co-regulate the phosphorylation of ERα at S167, and the levels of such phosphorylation are elevated in advanced EC. In the normal endometrium during the menstrual cycle, phosphorylation of ERα at S104, S118 and S167 synergizes with the phosphorylation of AKT at S473, while the phosphorylation of AKT at T308 regulates apoptosis in endometrial cells and arterioles (44). It has also been shown that the p38-MAKP-mediated signaling pathway induces the phosphorylation of ERα T311, which blocks ERα nuclear export and promotes the interaction between ERα and steroid receptor co-activator p160 (53).
Ubiquitination of ERα is mainly mediated by speckle-type POZ protein (SPOP), F-box protein 45 (FBXO45) and arylhydrocarbon receptor (AhR) (45,54,55). SPOP specifically recognizes the AF-2 domain of ERα and triggers ERα degradation through the ubiquitin-proteasome system, thereby inhibiting the development of EC (45). Similarly, the E3 ligase FBXO45 inhibits the progression of EC by mediating the ubiquitination and degradation of ERα (55). AhR has been shown to promote the ubiquitination and degradation of ERα via the assembly of a complex with cullin 4B (CUL4B) (54). In the CUL4B-AhR complex, AhR acts as a substrate recognition subunit that recruits ERα for degradation (54). By contrast, de-ubiquitination meditated by de-ubiquitinating enzymes, including ubiquitin-specific protease 14 and ubiquitin-editing enzyme A20, promotes the transcriptional activity of ERα by inhibiting its degradation, thereby leading to the development of EC (56,57). Regarding the acetylation of ERα, Wu et al (37) demonstrated that males absent on the first (MOF), also known as lysine acetyltransferase 8, mediates the acetylation of ERα, maintains the stability of ERα, and regulates the activity of ERα and its target genes. However, the study also indicated that MOF inhibits the proliferation of EC cells (37).
Classical E2/ERα signaling pathway
E2 and the ER are known to mediate two types of signaling pathways (58). One of these is mediated by nuclear ERs and is known as the genomic, classical or nuclear signaling pathway, and the other is mediated by membrane ERs and is referred to as the non-genomic, non-classical or extra-nuclear signaling pathway (58,59). Since the present review is focused on ERα, which belongs to the superfamily of nuclear receptors, only the classical E2/ERα signaling pathway is outlined here (Fig. 2).
The classical E2/ERα signaling pathway regulates the transcription of target genes through two different approaches, namely the classical and non-classical approaches, both of which can be divided into three steps, which differ most markedly in the third step (29). First, E2 either diffuses into the cell or is synthesized in situ inside the cell (60). Second, E2 enters the nucleus where it binds to and activates ERα to form a homologous or heterodimer of ERα (60). In the classic approach, the third step is that the activated ERα binds to E2 response elements (EREs), which comprise two AGGTCA motifs in a palindromic structure (39). The ERα-ERE complex promotes the formation of transcription initiation complexes and induces the transcription of target genes (39). In addition, in vivo pioneer factors initiate chromatin remodeling by opening up the chromatin structure to facilitate the binding of activated ERα with EREs, and co-regulators act synergistically with ERα to enhance or reduce the expression of specific genes, which play an important role in the occurrence and development of EC (61). However, in the third step of the non-classical approach, activated ERα does not directly bind to the promoter region of the target genes (29). Instead, ligand-bound receptor dimers first interact with other transcriptional factors, such as Fos or Jun, for transcriptional activation (29). ERα then binds to enhancer elements such as activating protein 1 and specific protein 1 in the promoter region of target genes to indirectly regulate the transcription of target genes (29).
The classical E2/ERα signaling pathway plays a key role in the occurrence and development of EC. For instance, ERα mediates E2-stimulated IL-6 production, which induces aromatase expression in stromal cells, thereby producing E2 in situ, which forms a positive feedback loop by which E2 promotes cancer progression (62). In addition, ERα also binds EREs and co-activators with ERRα (63). However, E2 downregulates the expression of ERRα at the mRNA and protein levels in Ishikawa cells by a mechanism involving ERα (64). ERRα competes with ERα for the same target gene loci and co-regulators, which interferes with the E2/ERα signaling pathway and thereby potentially suppresses the development of EC (39).
Roles of ERα in EC
ERα is generally considered to play a driving role in endometrial malignant transformation, which has three main aspects (Fig. 1) (65). First, upstream regulators of ERα regulate the transcriptional activity of ERα and thus influence the development of EC, especially cell proliferation (66). Second, ERα promotes the occurrence of EC together with other co-regulators (67). Third, ERα mediates EC proliferation, metastasis and apoptosis through its downstream proteins or target genes (68).
Upstream of ERα
Several upstream proteins of ERα participate in the occurrence and development of EC by affecting the transcriptional activity and expression of ERα (Table III). Since the proteins that mediate the post-translational modifications of ERα have been summarized previously in the present review, they are not covered again in this section.
Most of the upstream regulators promote the development of EC by enhancing the transcriptional activity of ERα. For example, the increased expression of co-activators p72 and amplified in breast cancer 1 (AIB1), as well as the interaction between erbB-2 and p72, have been suggested to enhance the interaction between E2 and ERα, thereby inducing the transactivation of ERα in EC; this suggests that transactivation of ERα induced by the overexpression of p72, AIB1 and erbB-2 may be involved in the development of EC stimulated by tamoxifen (69). Similarly, interaction between p21-activated kinase 4 (Pak4) and the E2/ERα signaling pathway has been shown to trigger the proliferation of EC cells (66). Specifically, E2 increases the expression and activation of Pak4 in ERα-positive EC cells via the PI3K/AKT/mTOR signaling pathway, and the accumulation of Pak4 and phosphorylated Pak4 in the nucleus promotes ERα transactivation, which enhances the transcriptional activity of ERα and ERα-dependent gene expression, leading to EC cell proliferation (66). Although these upstream regulators of ERα mainly promote the proliferation of EC, they have also been shown to have some effects on migration (70,71). In addition, protein kinase C α (PKCα) expression stimulates the ligand-independent activation of ER-dependent promoters to enhance the transcriptional capacity of ERα, thereby inducing endometrial proliferation (72). Furthermore, Frigo et al (73) showed that p38 promotes the proliferation of EC cells by stimulating ERα-mediated transcription via phosphorylation of the co-activator glucocorticoid receptor-interacting protein 1. With regard to migration, Kojima et al (74) demonstrated that claudin 6/Src-family kinase/PI3K-dependent AKT and serum- and glucocorticoid-regulated kinase signaling in EC cells targets ERα Ser518 in a ligand-independent manner to activate the transcriptional activity of ERα, thereby promoting tumor migration. In addition, mitogen-activated protein kinase kinase kinase 1 also induces the transcriptional activity of ERα through the N-terminal kinase of Jun and p38/Hog1, thereby stimulating the excitatory activity of 4-hydroxytamoxifen in the endometrium (75). There are also negative upstream regulators that inhibit the transcription of ERα and thus inhibit EC development. For example, the activation of Pten and subsequent inhibition of AKT have an inhibitory effect on several ERα-dependent pathways, which suppresses the development of EC (76). Moreover, Velard et al (77) demonstrated that Krüppel-like factor 9 inhibited the transcriptional activity of ERα in endometrial epithelial cells, and suggested that it acts at a node of the ERα genomic pathway to negatively regulate the proliferation of EC.
Another means by which upstream regulators regulate ERα is by affecting the expression of ERα. For example, Cheng et al (78) found that interleukin 17A induced the proliferation and metastasis of EC cells by promoting the expression of ERα. Likewise, human antigen R has been reported to increase the expression of ERα protein in Ishikawa cells, thereby promoting proliferation and inhibiting apoptosis (79). In addition, hyperglycemia-induced glucose transport protein 4 expression has been shown to increase the secretion of vascular endothelial growth factor (VEGF) and the expression of its receptor VEGFR via the upregulation of ERα, leading to accelerated epithelial-mesenchymal transition (EMT) in EC (80). Conversely, the inhibition of ERα expression delays the development of EC. For example, the downregulation of ERα by RAS association domain family 1 subtype A induces EC cell apoptosis and inhibits EC growth (81). However, some upstream regulators have been suggested to promote the development of EC by inhibiting ERα expression. For example, Tanwar et al (82) showed that reduced adenomatous polyposis coli activity in mouse uterine stromal cells led to transformation of the cells to a myofibroblast phenotype, which reduced ERα expression and induced EC. In addition, another study demonstrated that chemokine C-X-C motif chemokine ligand 8 (CXCL8) promoted the development of EC via the inhibition of ERα expression (83). Specifically, CXCL8 secreted by tumor-associated macrophages was shown to downregulate the expression of ERα in EC cells via homeobox 13, which was associated with the invasive ability of the cells (83).
Co-regulators of ERα
ERα contributes to the occurrence and development of EC via interactions with several proteins, such as receptor-binding cancer antigen expressed on SiSo cells (RCAS1), and by crosstalk with signaling pathways including the MAPK signaling pathway and insulin/insulin receptor signaling pathway (Table III) (84–87). For example, ERα and ERβ5 have been found to be co-expressed in the nuclei of endometrial adenocarcinoma cells, and to form heterodimers that enhance the hormone sensitivity of Ishikawa cells, thereby promoting the development of EC (88). Moreover, Bircan et al (89) demonstrated by immunohistochemical analysis that ERα expression was positively correlated with c-myc expression, suggesting that c-myc expression may contribute to the development of EC through ERα. With regard to specific effects, ERα has been suggested to influence the proliferation, invasion and metastasis of EC cells through interaction with various proteins or signaling pathways (86,90). Nakayama et al (90) observed an inverse correlation between ERα and 14-3-3σ, and speculated that these proteins have a synergistic effect that promotes EC proliferation and prevents apoptotic signal transduction in high-grade and middle-advanced endometrial adenocarcinoma. Furthermore, Zhou et al (84) demonstrated that the co-expression of RCAS1 and ERα may be involved in the development and metastasis of EC. Crosstalk between ERα and the MAPK signaling pathway has been suggested to be associated with the phenotypic plasticity of EC cells triggered by chronic 2,2′,4,4′-tetrabromodiphenyl ether exposure, which promoted EC tumor growth and attenuated the resistance of EC cells to chemotherapy (86). Similarly, crosstalk between the E2/ERα signaling pathway and the insulin/insulin receptor signaling pathway has been demonstrated to activate downstream PI3K/AKT/mTOR and MAPK signaling pathways, thereby contributing to occurrence and development of EC (85).
However, interactions between ERα and certain other proteins may inhibit EC cell proliferation (87,91). For example, Saito et al (87) suggested that an orphan nuclear receptor known as dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome gene 1 inhibits the proliferation and progression of EC by interacting with ERα in EC cells. Additionally, ERα and Forkhead-box A1, which is a tumor suppressor, have been demonstrated to interact in EC cells, and to inhibit the proliferation of EC cells (91).
Downstream of ERα
In addition to the upstream and co-regulators of ERα, downstream proteins or target genes are also involved in the promotion of EC development by ERα. These mainly contribute to three aspects: Proliferation, metastasis and invasion, and anti-apoptosis (Table III) (92–94).
Proliferation
ERα has been shown to induce the proliferation of EC cells via the promotion or inhibition of downstream substrates. For example, Chen et al (92) found that in EC cells, ERα binds to a half-ERE on the promoter of the gene encoding the stem cell protein Piwi-like RNA-mediated gene silencing 1 (PIWIL1), thereby upregulating the expression of PIWIL1 (92). The authors also found that upregulated PIWIL1 promoted the proliferation of EC cells, and that this effect was closely associated with hypomethylation of the PIWIL1 promoter (92). Similarly, ERα activates the promoter of the B-cell lymphoma/leukemia-2 (BCL2) gene to increase the transcription of BCL2, and also downregulates the expression of BCL2-associated X protein gene (BAX) via several miRNAs, thus leading to an imbalance of the BCL2/BAX ratio that promotes the proliferation of EC (95). In addition, in primary cultured human endometrial adenocarcinoma cells, E2 has been demonstrated to upregulate the expression of nucleophosmin 1 (NPM1) in a dose-dependent manner through ERα-mediated signaling rather than via ERβ, with the upregulation of NPM1 promoting the growth and proliferation of the cells and inhibiting their differentiation and apoptosis (3). It has also been shown that the E2/ERα signaling pathway inhibits the formation of an NPM-alternate reading frame complex, resulting in increased levels of NPM protein, which promote the proliferation of endometrial tissues and tumors (96). Additionally, ERα up- and downregulates the expression levels of cyclin D1 and p21, respectively, which induces dysregulation of the cell cycle and triggers the proliferation of EC cells (97). Furthermore, ERα has also been indicated to downregulate gap junctional intercellular communication (GJIC) mediated by the formation of gap junctions by connexins (Cxs), which is important in cell growth, differentiation, homeostasis and morphogenesis (98). Saito et al (98) showed that the activation of ERα by E2 stimulated cell growth and inhibited GJIC by inhibiting the expression of Cxs, leading to the proliferation of EC cells.
ERα can also promote the proliferation of EC cells via the activation of certain downstream signaling pathways (Fig. 2). For example, Hou et al (68) found that ERα overexpression promotes the phosphorylation of p85α, the regulatory subunit of PI3K, which activates the PI3K/AKT/mTOR signaling pathway, thereby increasing the proliferation, migration and invasion of EC cells. Moreover, another study demonstrated that the activation of ERα by E2 induces the nuclear localization and accumulation of fat mass and obesity-associated protein (FTO) through the PI3K/AKT/mTOR signaling pathway, which increases the proliferation of EC cells (99). Furthermore, the E2/ERα signaling pathway has been shown to increase the expression of miR-200c and decrease the expression of Pten, leading to activation of the PI3K/AKT/mTOR signaling pathway, thus promoting the proliferation of EC cells and inhibiting their apoptosis (100). Moreover, when stimulated by E2, cytoplasmic ERα forms a complex with protein kinase 2-α, which mediates the phosphorylation of Pten and promotes EC cell proliferation (101).
Invasion and metastasis
Invasion and metastasis are also affected by ERα through its downstream substrates, either directly or indirectly. In a Transwell experiment, Mizumoto et al (102) found that stimulation with E2 increased the invasive ability of Ishikawa cells, while the expression levels of matrix metalloproteinase (MMP)-1, −7 and −9 and the transcriptional factor ETS-1 were also enhanced. These results indicate that the activation of ERα stimulates EC cell invasiveness and tumor progression by promoting the expression of MMPs (102). In endometrial stromal cells and Ishikawa cells, E2 has been shown to promote cytoskeletal and membrane remodeling by the activation of focal adhesion kinase, thus increasing the motility and invasion of the cells (93). Furthermore, E2 upregulates the expression of ubiquitin-binding enzyme E2C via ERα in EC, which downregulates the expression of p53 and its downstream effector p21, thus promoting EC metastasis and invasion (103). In addition to playing a role in proliferation, the activation of FTO via E2/ERα also stimulates the invasion of EC cells through the PI3K/AKT/mTOR and MAPK signaling pathways (104). However, Wik et al (105) found that ERα-negative tumors are also associated with EMT, which is linked to the PI3K/AKT/mTOR signaling pathway. In addition to the aforementioned substrates, ERα also inhibits epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1), retinoblastoma protein-interacting zinc finger gene 1 (RIZ1) and urocortin to promote EC cell mobility (106–108). Using chromatin immunoprecipitation and dual-luciferase reporter assays, Yang et al (106) demonstrated that the E2/ERα signaling pathway downregulated EFEMP1 expression in EC cells by the direct binding of ERα to the EFEMP1 promoter. Given that EFEMP1 was also shown to inhibit EMT and the migration of EC cells via inhibition of the WNT/β-catenin signaling pathway, it was suggested that EFEMP1 may be an excellent candidate for EC therapy (106). The activation of ERα reduces the expression of urocortin, a protein that inhibits EC cell migration; therefore, the E2/ERα pathway may promote EC cell invasion and metastasis via this mechanism (108). Furthermore, RIZ1 has been shown to inhibit the migration and invasion of EC cells in vivo and in vitro (107). Yang et al (107) showed that E2 downregulated the expression of RIZ1 in EC cells, which promoted the development of EC. They also found that the selective ERα antagonist ICI182780 reversed this effect, suggesting that a potential mechanism by which RIZ1 promotes EC involves the E2/ERα signaling pathway (107).
Anti-apoptosis
There have been only a few studies on ERα in terms of anti-apoptosis and drug resistance. It has been shown that by directly binding to p53, ERα inhibits the transcriptional activation of p53, which downregulates the inhibitory effect of p53 on survivin (94). Survivin inhibits apoptosis through a variety of mechanisms, including directly binding to and inhibiting caspase-3 and caspase-9 (109). In a study of Ishikawa and HEC-265 cells, Chuwa et al (110) found that E2 significantly induced the co-expression of ERα and survivin in EC cells, which reduced the apoptosis of these cells. In addition, during the G1 phase of EC, the E2/ERα signaling pathway has been shown to promote the translocation of phosphorylated AKT into the nucleus and thereby inhibit the apoptosis of EC cells (111). Moreover, it has been suggested that ERα may enhance the interaction between STAT3 and the apoptosis regulator BCL-extra large, which is crucial for the development of endometrioid adenocarcinoma (112). Furthermore, ERα expression has been indicated to influence the pro-apoptotic or anti-apoptotic effects of abnormally expressed Cx43 and Cx26 in EC (113). Regarding drug resistance, Abe et al (114) found that ERα upregulates the expression of BCL2-associated athanogene 3 (BAG3) in EC cells, inhibits the expression of miR-29b, and increases the expression of Mcl-1, which is a downstream mediator of BAG3. In addition, the authors also found that ERα overexpression improves the survival of EC cells in the presence of cisplatin, suggesting that ERα may enhance the resistance of EC cells to anticancer drugs via the overexpression of BAG3 (114).
Clinical application
ERα is used as a therapeutic target for EC, and several drugs targeting ERα are currently being applied for the treatment of EC. In addition, ERα has a role as a good prognostic indicator for EC (Table IV) (12,115).
Selective ER modulators including tamoxifen and raloxifene are the most intensively studied anti-ERα agents in EC. Tamoxifen affects the interaction of ERα with co-regulatory factors and alters the DNA binding characteristics of ERα in EC tissue (116). Tamoxifen contributes to the proliferation and carcinogenesis of EC via the promotion of ERα transcriptional activity through the constitutional activation of MAP kinase signaling (117). Moreover, SRC kinase promotes the role of tamoxifen in EC through the AKT kinase-induced phosphorylation of ER S167, thereby stabilizing ER promoter interactions and increasing ERα signaling (118). However, despite increasing the risk of EC, tamoxifen is also an effective low-toxicity drug for the treatment of advanced or relapsing EC (119). Tamoxifen exerts excitatory or antagonistic effects on ERα through the tissue-specific expression of co-activators and -inhibitors of receptors (119). The development of EC associated with tamoxifen has been suggested to be due to the MAPK signaling pathway increasing the transcriptional activity of ERα through AF-1 (117). It was these negative effects of tamoxifen that drove the development of raloxifene (120). Raloxifene not only has the same mechanism as tamoxifen to inhibit ERα and inhibit the proliferation of EC, but also induces mitochondria-mediated apoptosis of EC (120). The selective ER downregulator ICI-182780 and genistein significantly reduce the expression level of ERα induced by E2 (121). Boisen et al (122) found that ICI-182780 binds to ERα to inhibit E2, and also competently binds to the LBD of ERα and induces ERα degradation through the ubiquitin-proteasome system. However, in primary EC, splicing variants and point mutations present in the LBD are associated with hormone-independent ERα activity, which can produce ligand-independent or anti-E2 therapy resistance (123). Similar to ICI-182780, clomiphene citrate has been shown to reduce the ERα protein level via induction of ubiquitin-proteasome system without affecting the ERα mRNA level in Ishikawa cells (124). Arsenic trioxide, however, inhibits both ERα mRNA and protein expression in a dose-dependent manner by promoting the rapid phosphorylation of p42/p44 in the MAPK signaling pathway, thereby exhibiting an anti-EC effect (125). The natural dietary flavonoid kaempferol effectively targets ERα-mediated oncogenic signaling pathways to induce the death of EC cells, not only via the inhibition of ERα and survivin proteins, but also by the induction of p53 (110). Metformin exhibits an inhibitory effect on the E2-induced enhanced proliferation of Ishikawa cells that is weakened or partially reversed in ESR1 knockout cells, indicating that ERα mediates the inhibitory effect of metformin on the proliferation of EC cells (97). It has been suggested that this effect may be attributed metformin reducing the expression of ERα at the protein and mRNA levels, resulting in a reduction in the expression of the ERα-target genes keratin-19 and WNT-1 (126). Compared with anti-ERα treatment alone, the dual targeting of ERα and ERRα in the treatment of EC has an improved therapeutic effect, because this maximizes the growth inhibitory and pro-apoptotic effect on EC cells (127). DY131, a selective ERRγ agonist, inhibits the growth of ERα-positive EC cells but promotes the growth of ERα-negative EC cells (128). In addition, melatonin has been shown to enhance the anti-EC effect of chemotherapy, particularly paclitaxel, by the inhibition of ERα expression in Ishikawa cells (129). Furthermore, a combination of S-farnesylthiosalicylic acid and medroxyprogesterone acetate was demonstrated to inhibit growth and increase cell death in type II EC cells by decreasing the mRNA expression of the ERα-mediated progesterone receptor (PR), c-fos and ps2/trefoil factor 1 (130).
A number of very promising targets and drugs for the treatment of EC have been identified. Miki et al (131) showed that heterogeneous nuclear ribonucleic protein K (hnRNPK) immunoreactivity in normal endometrium in the proliferative phase was higher than that in the secretory phase, and the expression levels of both ERα and hnRNPK were higher in benign endometrial tissue than in EC. In both normal and cancerous tissues, the median hnRNPK immunoreactivity was significantly increased in cases with high ERα, which was significantly associated with improved disease-free survival (DFS) and overall survival (131). Based on these results, it was proposed that hnRNPK interacts with ERα to regulate changes in the endometrium during the menstrual cycle, thus having the ability to inhibit the malignant behavior of EC (131). Krakstad et al (132) found that the GPER protein is significantly associated with ERα in GC, and a loss of GPER in patients with ERα-positive GC is associated with a poor prognosis. Additionally, using bioinformatics they found that HDAC inhibitors may be promising drugs for the treatment of ERα-positive EC with GPER deletion (132). Although E2 activates NPM via ERα, increased NPM expression inhibits ERα (133). Since strategies to promote ERα re-expression may allow patients with relapsed EC to resume endocrine therapy, inhibition of NPM may represent a strategy to promote ERα re-expression and ultimately restore the sensitivity of EC to hormone therapy (133). Moreover, the expression of ERα in EC has been found to negatively correlate with human phosphatidylethanolamine-binding protein 4 (hPEBP4), PKCα and antisense oligodeoxyribonucleotides against ERα, suggesting that hPEBP4, PKCα and nucleic acid therapeutics may counter the ERα and serve as potential agents against the proliferation of EC cells (134–136).
Given the widespread clinical application of endocrine therapy specific to ERα, ERα can be used as a good prognostic indicator in EC (22). Among patients with EC, those with ERα-positive tumors have relatively good survival and the high expression of ERα is associated with an improved DFS in both type I and II EC (137,138). Through the analysis of 214 patients with endometrial adenocarcinoma, Mylonas (139) found that the loss of ERα was associated with poor survival. Furthermore, in another study ERα mRNA upregulation was shown to be an indicator of good prognosis in patients with EC (115). The expression of ERα is associated with the stage, histological grade and survival of EC (140), and ERα upregulation is considered to provide prognostic information independent of tumor grade and stage in women with EC (141). Although Mylonas did not find ERα to be an independent factor affecting survival in patients with endometrial adenocarcinoma, it was suggested that the combined analysis of ERα and ERb may be used to identify high-risk patients with endometrioid adenocarcinoma (139). The uptake of 16α-[18F]fluoro-17β-estradiol (FES) is closely correlated with ERα expression, and the 2-[18F]fluoro-2-deoxy-D-glucose (FDG)/FES ratio is negatively correlated with ERα expression, both of which can reflect the differentiation degree of EC (142). Given the high expression of ERα in low-grade EC, it was suggested that FES positron emission tomography in combination with FDG can be used to noninvasively assess ERα distribution and function, and has potential in the prognosis of EC and determination of its treatment (142). As in EC, it has also been proposed that ERα could be used as a prognostic indicator in serous uterine carcinoma. The expression of ERα in serous uterine carcinoma is associated with advanced stage, and a prognosis that is significantly worse than that of serous uterine carcinoma without ERα expression (143).
Discussion
The role of ERα in EC is becoming increasingly clear. In general, ERα, as a transcriptional factor, is an oncogenic factor in EC. ERα regulates transcriptional activity with modulation by upstream co-regulatory factors, and then promotes transcription of its downstream target genes via the E2/ERα signaling pathway, thus promoting the occurrence and development of EC, with the induction of proliferation, invasion, metastasis and anti-apoptosis effects.
However, two important aspects of ERα in EC merit further investigation. One is that the progressive loss of ERα seems to be associated with the progressive malignancy of EC (89). That is, highly differentiated EC typically retains ERα expression in the early stages, while in advanced stages, poorly differentiated EC tends to lack this receptor (144). Pathirage et al (145) found that ERα expression was significantly elevated in grade 1 EC compared with normal tissues and higher grade EC, and observed a significant negative correlation between ERα expression and the grade of EC. Using immunohistochemistry, Hu et al (97) observed that the positive expression rate of ERα was higher in patients with moderately and highly differentiated EC than in those with poorly differentiated EC, and showed that ERα expression was higher in the early stage of EC development compared with the late stage of EC. Therefore, they hypothesized that ERα promotes endometrial dysplasia and the early progression of EC through interaction with E2 (97). However, they observed that ERα sensitivity to E2 changed and more ERα-negative EC cells appeared during EC progression, resulting in a lower expression of ERα in advanced EC (97).
The other key aspect of ERα in EC is that it may also act as a tumor suppressor. It has been shown that ERα localized in the cytoplasm promotes cardiovascular protection in mice but does not promote the occurrence and development of EC (146). Furthermore, it has been demonstrated that the ERα-mediated signaling pathway regulates the expression of olfactomedin 4 (OLFM4), and that the expression of OLFM4 and ERα are positively correlated (147). While the increased expression of OLFM4 during the development of EC is associated with the differentiation of endometrioid adenocarcinoma, the downregulation of OLFM4 promotes the proliferation, migration and invasion of EC cells, and is associated with a reduced survival rate in patients with endometrioid adenocarcinoma (147). In addition, ERα blocks the formation of tumor blood vessels (148). The high levels of ERα in EC have been indicated to inhibit tumor growth via the regulation of angiogenic factors such as integrin αvβ3, thereby reducing the blood supply (148,149). In addition, ERα interacts with the Sp3 protein, which inhibits VEGF expression and thus blood supply in EC (150). Moreover, Joshi et al (151) observed endometrial hyperplasia/carcinoma in 88.9% of Pten+/− ERα−/− mice. These mice also exhibit a high incidence of carcinoma in situ and invasive carcinoma, suggesting that EC can develop in the absence of ERα (151).
In addition to ERα, there are some ESR1 gene, ERα mRNA and ERα protein variants that influence the occurrence and development of EC (152–154). Wedren et al (152) found that ESR1 intron variants are associated with EC risk. Furthermore, Jazaeri et al (153) detected ERα mRNA variants in all endometrial samples, including premenopausal and postmenopausal endometrial samples, but only observed ERα protein splicing variants in EC. ERα36, a variant of ERα protein, triggers the activation of epidermal growth factor receptor-associated extracellular signal-regulated kinases, which play a carcinogenic role in EC (154). Similarly, the ERα variant d5 exhibits a dominant positive activity on ERα-regulated promoters, which maintains the expression of E2-responsive genes in the absence of E2, resulting in EC (155). Therefore, further exploration of variants of ERα provides a feasible direction for further understanding the pathogenesis of EC.
Although ERα is the most common target of targeted therapy in breast cancer, anti-ERα therapy has shown inconsistent results in EC, with very limited therapeutic efficacy and sometimes even an increased risk of cancer (123). Since the study based on TCGA database in 2013 (156), a new molecular classification of EC has emerged, which is mainly based on overall mutational burden, p53, polymerase-epsilon (POLE), Pten mutations, microsatellite instability and histology, which helps to refine the prognosis of EC (156–158). It divides EC into four molecular subtypes: POLE ultra-mutated, microsatellite instability hyper-mutated, copy-number low and copy-number high (157,158). Due to the high cost of the genetic analysis of POLE, another simplified version of molecular typing is commonly used in clinical practice, which divides EC into POLE-mutant, mismatch repair deficient, no specific molecular profile (NSMP) and p53-aberrant subtypes (157). Among these, only NSMP usually comprises ERα and PR, while in the other three subtypes, hormone receptors are usually absent (157,159). In NSMP, the level of copy number alterations is low, the tumor mutation burden is moderate, and mutation mainly occurs in the PI3K/AKT/mTOR and WNT/β-catenin signaling pathways (157). Targeted therapy for ERα or hormonal therapy, alone or in combination with mTOR inhibitors, is indicated to further improve outcomes in patients with NSMP (160). By contrast, a range of treatments targeting ERα may not have much effect on the other three molecular subtypes. Clinically, in addition to targeting ERα, a number of drugs target other biological molecules: E2, including anastrozole and letrozole; PR, such as medrysone; VEGF, including bevacizumab and lenvatinib; mTOR, such as everolimus and ridaforolimus; and programmed cell death protein, for example, pembrolizumab and dostarlimab in the treatment of EC (161–165). Studies have shown that the combination of tamoxifen with anastrozole, bevacizumab, everolimus or pembrolizumab can be used to control the proliferation and metastasis of breast cancer (166–169). However, in EC, there have been few studies on the combination of anti-ERα drugs with other drugs, and it is not clear whether they affect the prognosis of EC. Furthermore, when combined with chemotherapy drugs or mTOR inhibitors, anti-ERα drugs can have serious side effects and these occur frequently (170). Therefore, it is necessary to find improved ERα-targeting drugs or combinations of drugs in future studies, so as to further improve the prognosis of patients and reduce the occurrence of side effects.
Acknowledgements
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Availability of data and materials
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Authors' contributions
MY and XJ conceived the study. YG, XN and JL collated the data. YG, XN and JL wrote the manuscript. MY and XJ revised and edited the manuscript. Data authentication is not applicable. All authors read and approved the final version of the manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
AbbreviationsAF
activation function
AhR
arylhydrocarbon receptor
BAG3
BCL2-associated athanogene 3
BAX
BCL2-associated X protein gene
BCL2
B-cell lymphoma/leukemia-2
Cx
connexin
DBD
DNA binding domain
EC
endometrial carcinoma
EFEMP1
epidermal growth factor-containing fibulin-like extracellular matrix protein 1
EMT
epithelial-mesenchymal transition
ER
estrogen receptor
ERE
E2 response element
ERR
ER-related receptor
E2
estrogen/17-β-estradiol
FBXO45
F-box protein 45
FDG
2-[18F]fluoro-2-deoxy-D-glucose
FES
16α-[18F]fluoro-17β-estradiol
FTO
fat mass and obesity-associated protein
GJIC
gap junctional intercellular communication
GPER
G protein-coupled ER
hnRNPK
heterogeneous nuclear ribonucleic protein K
hPEBP4
human phosphatidylethanolamine-binding protein 4
LBD
ligand-binding domain
MMP
matrix metalloproteinase
NPM
nucleophosmin
OLFM4
olfactomedin 4
Pak4
p21-activated kinase 4
PKCα
protein kinase C α
PPARγ
peroxisome proliferator-activated receptor γ
RCAS1
receptor-binding cancer antigen expressed on SiSo cells
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Structure and regulation of ERα. ERα is composed of six domains, A-F, and had upstream, downstream and co-regulators. The upstream and downstream factors include promoters and inhibitors. These regulators can affect the role of ERα in endometrial cancer. ERα, estrogen receptor α.
Signaling pathways associated with ERα. ERα is mainly involved in the E2/ERα signaling pathway, which includes classical and non-classical approaches. In addition, ERα regulates the PI3K/AKT/mTOR, MAPK, WNT/β-catenin and JAK/STAT signaling pathways. ERα, estrogen receptor α; E2, estrogen/estradiol.
Mutation sites and frequency of estrogen receptor 1 in gynecological tumors.