Luis Molina Calistro1*
Yennyfer Arancibia1
Marcela Alejandra Olivera1
Sigrid Domke2
Rodrigo Flavio Torres1*- 1Facultad de Medicina y Ciencia, Universidad San Sebastián, Puerto Montt, Chile
- 2Facultad de Ciencias para el cuidado de la salud, Universidad San Sebastián, Puerto Montt, Chile
G Protein-Coupled Estrogen Receptor 1 (GPER-1) is a membrane estrogen receptor that has emerged as a key player in breast cancer development and progression. In addition to its direct influence on estrogen signaling, a crucial interaction between GPER-1 and the hypothalamic-pituitary-gonadal (HPG) axis has been evidenced. The novel and complex relationship between GPER-1 and HPG implies a hormonal regulation with important homeostatic effects on general organ development and reproductive tissues, but also on the pathophysiology of cancer, especially breast cancer. Recent research points to a great versatility of GPER-1, interacting with classical estrogen receptors and with signaling pathways related to inflammation. Importantly, through its activation by environmental and synthetic estrogens, GPER-1 is associated with hormone therapy resistance in breast cancer. These findings open new perspectives in the understanding of breast tumor development and raise the possibility of future applications in the design of more personalized and effective therapeutic approaches.
1 Introduction
Breast cancer is a malignant disease that originates in the cells of the breast tissue. In this type of cancer, breast cells multiply abnormally and uncontrollably, forming a tumor or mass in the breast. Breast cancer comprises a variety of subtypes, and its aggressiveness and behavior can vary significantly between patients, often posing clinical challenges in terms of diagnosis and treatment (1). Morphologically, the most common type of breast cancer affects the ducts responsible for milk transport (ductal cancer), while the second most frequent form starts in the lobules, i.e. the milk-producing glands (lobular cancer).
Breast cancer is the most common form of cancer in women (2) but can also affect men (3). Conventional biomarkers used to assess the disease include estrogen (ER) and progesterone receptors (PR), as well as evaluation of the Human Epidermal Growth Factor Receptor 2 (HER2) and Epidermal Growth Factor Receptor (EGFR) genes, along with the BRCA1 and BRCA2 genes. In addition, biomarkers such as Ki-67 and p53 provide additional information on tumor aggressiveness (4). The presence or absence of the ERα receptor in the tumor cell allows the cancer’s categorization as sensitive or insensitive to estradiol, respectively. This categorization is critical for medical decisions in the process of diagnosis and treatment.
Although timely diagnosis and the development of effective therapies have led to significant progress towards reducing breast cancer mortality. The molecular variability, within and between patients (1), underlie phenotypic and behavioral changes in tumor cells. These changes drive the cellular resistance to anticancer therapies, rendering breast cancer as one of the worldwide leading causes of cancer-related deaths (5). Hence, new biomarkers that contribute to improving the diagnostic and treatment of breast cancer patients represents a major goal in breast cancer research.
The Hypothalamus-Pituitary-Gonads (HPG) axis promotes organic development, contributing to reproductive function, as well as to the menstrual cycle and breast development in women. An important part of these physiological responses is mediated by estradiol through its nuclear specific receptors, ERα and ERβ. However, interaction of estradiol with the membrane G Protein Coupled Estrogen Repector-1 (GPER-1) contributes to the physiological regulation of the HPG axis, sexual hormone levels and to the fine mechanisms of estradiol release (6). In fact, the expression of GPER-1 has been detected in key tissues in human hormonal communication, such as the hypothalamus, the pituitary gland, the gonads (especially the ovaries) and the mammary gland (Figure 1). Importantly, alterations in the regulation of the neuroendocrine axis generate relevant effects on breast cancer development (7). In some cases, GPER-1 is overexpressed in tissues within the HPG axis, dysregulating the estrogenic signaling pathways that relay on GPER-1 receptor activity. These alterations ultimately contribute to cancer cell proliferation (8, 9). GPER-1 is also expressed in breast cancer stem cells. Cancer stem cells exhibit stem cell-like properties in terms of self-renewal and differentiation. These cells contribute to tumor growth, metastasis, and resistance to therapeutic treatments (10). A study using xenografts derived from patients with ER-/PR+ breast cancer (CSCM) has shown that GPER-1 is significantly expressed in these cells. In fact, GPER-1 silencing reduces the pluripotency characteristics of this cell type. Moreover, activation of GPER-1 by tamoxifen promotes Protein Kinase A (PKA)/Bcl-2-antagonist of cell death (BAD) phosphorylation, which maintains stemness and viability characteristics in CSCMs (Y.-T. 11).
Figure 1. Overexpression of GPER-1 during Epithelial-Mesenchymal Transition in Breast Cancer. Prolonged exposure to noxious stimuli, such as xenoestrogens or other estrogenic molecules, creates a favorable tumor environment for epithelial-mesenchymal transition in breast cancer cells. This is characterized by increased expression of GPER-1 in the tumor cell, leading to increased activity of signaling pathways dependent on this receptor.
Since the identification of GPER-1 as an estrogen receptor, it has attracted increasing interest due to its involvement in the pathophysiology of various chronic diseases, including metabolic, nervous, cardiovascular and cancer diseases (12). Interestingly, GPER-1 also interacts with molecules that exhibit structural homology with estradiol, which could contribute to breast cancer development and its relation to environmental pollution (13).
In summary, recent research indicates that the involvement of GPER-1 in the regulation of the HPG axis is extremely relevant in the context of breast cancer, as alterations in hormonal signaling promote tumor growth and cancer progression. Understanding these interactions may provide crucial information for developing personalized therapeutic strategies.
2 The emerging role of GPER-1 in estradiol-dependent signaling
The discovery GPER-1, also known as GPR30, in the 2000’s marked an important milestone in estrogenic signaling research (14). This finding has provided a novel insight into how estrogens interact with cells, allowing a greater understanding of estrogen versatile role in health and disease.
Early indications about GPER-1 activity involved the observation of rapid intracellular responses to estrogen (15) included calcium mobilization and activation of protein kinases. Both processes occur within seconds or minutes, contrasting to the slower genomic responses that require regulation of gene transcription driven by the activation of estrogen nuclear receptors (16).
GPER-1 is now known to play a crucial role in intracellular signal transduction in response to estradiol (17β-estradiol or E2), but also to other types of physiological estrogens, such as estrone (E1) and estriol (E3) (17). Moreover, activation of GPER-1 by several estrogenic compounds of natural (such as phytoestrogens) and synthetic origin (such as bisphenols) has also been reported (18). In addition, tools such as the GPER-1 specific synthetic agonist, G1, together with the antagonist compounds G15 and G36, have been used to assess GPER-1 function in different cells and animal models (17, 19). These compounds are derived from quinolones, and their functional groups give them bioactive properties. Since their discovery, these pharmacological tools have been essential for the development of new strategies focused on the characterization of GPER-1 signaling (10, 20, 21). New computational techniques have enabled detailed ligand analysis and facilitated the design of new drugs targeting GPER-1. This has contributed significantly to the understanding of the underlying molecular mechanisms, as well as to the identification of potential modulators and therapeutic candidates (22).
In triple-negative MDA-MB-231 and HCC 1386 cells, GPER-1 silencing using a specific siRNA reduces the invasiveness of breast tumor cells. Furthermore, this silencing increases sensitivity to tamoxifen through estrogen receptor beta (23). A recent investigation in estradiol-sensitive breast cancer cell lines resistant to 4-hydroxytamoxifen (4-OHT), the major metabolite derived from tamoxifen, showed that silencing of Cysteine-Rich Angiogenic Inducer 61 (CYR61) expression resulted in a significant decrease in cell invasion and re-sensitization to 4-OHT, suggesting that CYR61 suppression could be a promising therapeutic strategy to improve the treatment of tamoxifen-resistant breast cancer (24).
GPER-1 can mediate both genomic and non-genomic responses. Its activation leads to diverse intracellular events, such as transactivation of the epidermal growth factor receptor (EGFR) (25). EGFR transactivation leads to the rapid of mitogen-activated protein kinases (MAPKs), especially extracellular signal-regulated kinases 1 and 2 (ERK1/2), phosphorylation of phospholipase C (PLC) and phosphatidylinositol- 3-kinase (PI3K). Ultimately, adenyl cyclase (AC) stimulation directs the intracellular mobilization of Ca2+ (26, 27). EGFR is a key player in the regulation of cell proliferation and survival. Its interaction with GPER-1 triggers a signaling cascade involving the activation of kinases which can modulate the activity of ryanodine channels (RyR1 and RyR2) of the endoplasmic reticulum (28). Subsequent intracellular calcium release plays a crucial role in cell proliferation and in the acquisition of drug-resistant phenotypes in tumor cells, making this pathway a promising therapeutic target (29). In addition, GPER-1 regulates estradiol-related gene expression through activation of PI3K and pERK1/2, mediating cell survival and proliferation signals (30).
GPER-1 activation complexly modulates the expression of multiple microRNAs in breast cancer (31). MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression at the post-transcriptional level by binding to messenger RNAs (mRNAs) and inhibiting their translation or promoting their degradation. For example, miRNAs such as miR-9-5p, miR-10b-5p and miR-21-5p are overexpressed and act as oncogenes, promoting GPER-1 expression and suppressing tumor genes such as PTEN and TIMP3, which in turn are associated with increased resistance to treatments (32–34). On the other hand, miRNAs such as miR-205-5p and miR-206 exert tumor suppressor effects by inhibiting oncogenic signaling pathways such as Ras/Raf/MEK/ERK and reducing the invasiveness of cancer cells (35). These findings could be useful not only for the development of new therapeutic strategies, but also for understanding treatment failure in cancer patients.
On the other hand, it is well established that ERα plays a gravitating role in the development of breast cancer. Of note, ERα presence and activity are closely related to the growth and proliferation of tumor cells (36). Thereof, tumors expressing this receptor are typed as ERα-positive, meaning that they are stimulated by estradiol, the most potent biological form of estrogen (4). These cancers correspond to 60%-70% of breast cancer cases (37). On the other hand, overexpression of ERα favors the stabilization and repair of the genome of tumor cells (38, 39). The ERα-positive classification is relevant for choosing a therapeutic strategy. Tamoxifen or aromatase inhibitors are the general choice in these cases, as the objective is to block or reduce ERα activity. ERα-negative breast tumors do not respond to hormone therapy and tend to grow and proliferate more rapidly, have a higher propensity to metastasize, and have a limited response to chemotherapy, resulting in a less favorable prognosis.
3 GPER-1 in the communication of the hypothalamic-pituitary-gonadal axis, new implications in breast cancer.
3.1 Role of GPER-1 in the endocrine regulatory axis HPG
The ubiquity of GPER-1 in various body tissues suggests its fundamental role in organ homeostasis and dysregulation. Numerous studies have demonstrated its involvement in the regulation of key physiological systems, such as the cardiovascular and immune systems. For a comprehensive review of the multiple functions of GPER-1 in these contexts, please refer to (12). Until recently, the cellular response to estradiol in the nervous and reproductive systems were thought to rely exclusively on the classical nuclear receptors. However, the discovery of GPER-1 has revealed that a significant part of estrogenic responses may result from the activity of this membrane receptor (12). Importantly, the responses commanded by GPER-1 may be different in males and females, due to changes in their expression levels, especially during the estrous cycle (40).
GPER-1 has been identified at various locations in the central nervous system, suggesting a broad involvement of this receptor in both behavioral and reproductive processes. For instance, GPER-1 has been detected in different hypothalamic cell types, including neurons, astrocytes, and oligodendrocytes (41).
Furthermore, studies in female rats have determined that GPER-1 is related to estradiol activity on the functions of the anterior hypothalamus, ranging from feeding behavior to sexual receptivity (41). Hence, this receptor could collaborate in several of the biological responses regulated by the hypothalamus, such as sleep, feeding, stress response and endocrine regulation (42). In addition, GPER-1 expression has also been detected in the amygdala and dorsal hippocampus, modulating anxiety, social recognition, and spatial memory (40). Opening the interrogation of its role in other neuronal processes.
The presence of GPER-1 has recently been determined in lactotrophs, a cell type of adenohypophysis whose main function is to synthesize the hormone prolactin. Interestingly, the GPER-1 agonist G1 induced a rapid stimulation of prolactin secretion, both in vitro and ex vivo. This effect was prevented by the GPER-1 antagonist G36 (43). Furthermore, GPER-1 is expressed in anterior pituitary gonadotroph cells. Modulating the response of these cells to gonadotropin-releasing hormone (GnRH) and contributing to the negative feedback exerted by estradiol on luteinizing hormone (LH) secretion (44).
LH plays a crucial role in the reproductive system of both males and females. In males, GnRH stimulates Leydig cells in the testis for the synthesis of testosterone, which together with follicle-stimulating hormone (FSH) promotes the process of spermatogenesis (45). GPER-1 has also been identified in testicular tissue. Somatic, Leydig and Sertoli cells, as well as germ cells, including spermatogonia, spermatocytes and spermatids show GPER-1 expression (26) (Table 1). Furthermore, in Leydig cells, estradiol directs a GPER-1-dependent down-regulation of testosterone synthesis (20-30%) relative to untreated Leydig cells (46). Immature Sertoli cells survival is enhanced by stimulation with estradiol or G1. Increasing anti-apoptotic signals through the GPER-1/EGFR/mitogen-activated protein kinase3/1 (MAPK3/1) pathway (47, 48). In this line, it has been observed that nanomolar concentrations of the synthetic estrogenic compound bisphenol A (BPA) increases the proliferation rate of mouse immature Sertoli cells. The increase in the proliferation of this cells involves both GPER/EGFR/ERK1/2 and ERα/β/ERK1/2 pathways (49). Altogether, these findings position GPER-1 as a mediator of the estrogen-dependent testicular development and spermatogenesis.
Table 1. GPER-1 and its role in the HPG axis.
In females, luteinizing hormone (LH) stimulates ovulation and subsequent corpus luteum formation (54). The involvement of GPER-1 in ovogenesis has been the subject of study in several vertebrate species (55, 56). For instance, GPER-1 expression has been detected in the oocyte membrane, especially as it reaches a higher degree of maturation (50). More recently, follicle stimulating hormone (FSH) has been found to stimulate aromatase enzyme expression and estradiol biosynthesis in mouse cumulus-oocyte complexes (COCs). Estradiol then activates the GPER-1/ERK1/2 pathway promoting oocyte expansion and maturation (57).
Granulosa cells are crucial components of ovarian follicles, surrounding and providing nutritional support to developing oocytes. Interestingly, expression of both FSH receptor (FSHR) along with GPER-1 has been demonstrated in this cell type (51). During follicular maturation, in response to FSH released by the adenohypophysis, granulosa cells convert androgens to estradiol for regulation of the menstrual cycle and preparation of the uterus for potential implantation. Recently, the formation of heteromeric complexes between GPER-1 and FSHR at the cell membrane has been demonstrated, contributing to the viability of granulosa cells (52). GPER-1 and FSHR are estimated to collaborate by generating a signaling network that promotes gametogenesis (53).
Although mice lacking GPER-1 do not show clear alterations in reproduction or fertility (58), the evidence indicates that GPER-1 contributes to the synchronization of sex hormone release, particularly estradiol, modulating its physiological effects on peripheral and reproductive tissues. On the other hand, the GPER- 1 deficient murine model allowed linking this receptor to the development and metastatic capacity of breast cancer (59).
Several investigations have evidenced the impact of various compounds with estrogenic activity on the hypothalamic-pituitary axis, although the interaction of these compounds with GPER-1 is not entirely clear, some studies suggest an active role of GPER-1 in the hypothalamic-pituitary axis, in the context of exposure to molecules with estrogenic activity (60), opening the possibility of new avenues of research on unconventional mechanisms of hormone action (61). In addition, bisphenol-GPER-1 interaction has been associated with male infertility (62). The results of future studies could reveal complex molecular mechanisms and their implications in endocrine pathophysiology.
3.2 GPER-1 in the endocrine disruption and pathophysiology of breast cancer
GPER-1 also is expressed in different types of mammary cells, including epithelial cells, myoepithelial cells, and stromal cells, being involved in normal mammary gland development and function (63). In addition, GPER-1 has also been observed to be associated with several pathological processes, especially breast cancer.
Aging is considered one of the main risk factors for breast cancer development (64). With age, the ability to repair DNA decreases, making cells prone to cancer-promoting genetic changes. In addition, the ability of the immune system to respond to tumor cells is altered during aging (65). Another important factor corresponds to alterations in the regulation of hormone release. During menopause, which marks the end of menstruation, the ovaries decrease the biosynthesis of sex hormones (66). However, during a time corresponding to the menopausal transition (MT), the adenohypophysis generates a monotropic (constant) increase in FSH in response to the ovarian reserve reduction. During MT estradiol levels also increase, before decreasing significantly during menopause (67). However, not all estrogenic hormones are downregulated during this period. One example is estrone, which is mainly produced in adipose tissue. Hence, the decrease in estradiol during menopause does not mean a total reduction in estrogen exposure (Figure 1).
Another important factor in breast cancer development is the regulation exerted by the tumor microenvironment. Tumor microenvironment may promote carcinoma cells to change their epithelial nature to mesenchymal characteristics, a phenomenon known as epithelial-mesenchymal transition (EMT) (68). Importantly, recent research indicates that estrone induces EMT, thus facilitating the invasiveness of breast cancer (69). Furthermore, it has been suggested that, in postmenopausal women, the relationship between estrone and estradiol may be an important factor in breast cancer risk (69). Hence, estrone, by acting as a GPER-1 agonist (70), could contribute to the development of estrogen-sensitive breast cancer. GPER-1 activation correlates with increased expression of mesenchymal markers such as vimentin and N-cadherin (71). In turn, estrone, a major GPER-1 agonist (17), has been implicated in promoting EMT (69). Exposure of breast cancer cells to estrone induces the expression of EMT-associated transcription factors, such as Snail and Slug, and promotes the generation of more invasive cells (Y. 72). These findings suggest a causal relationship between GPER-1 activation by estrone and EMT induction, underscoring the potential role of this receptor in tumor progression and metastasis. Furthermore, pharmacological inhibition of GPER-1 or inhibition of its expression by interfering RNA (siRNA) techniques reverses EMT and reduces the invasiveness of cancer cells (73).
On the other hand, hormone replacement therapy, aimed at preserving the beneficial effects of estradiol on female physiology. Particularly regarding metabolism and cardiovascular health (74), could also have undesirable side effects, contributing to the development of breast cancer (75). Similarly, the use of oral contraceptives, consisting of a combination of estrogens and progestogens, is considered a risk factor for the development of breast cancer (76). Increased exposure to estrogens alters the physiological regulation of sex hormone release, disrupting the signaling commanded by estrogen receptors and promotes hormone-dependent cancer development (77). In fact, it has been observed that a significant number of estradiol-sensitive (ERα-positive) breast cancer cases co-express GPER-1 (78), which is associated with worse prognosis and diminished survival of patients, even in those patients treated with tamoxifen (78, 79).
Dysregulation of estrogen signaling may play a critical role in tumor progression by providing an environment conducive to tumor growth and facilitating metastasis (80). Increased expression of GPER-1, as well as its aberrant activation, is associated with several hormone-dependent cancers, including cervical (81), prostate (82), testicular (26), breast (83), lung (81) and glioblastoma (84). However, in some types of reproductive tumors, antitumor activity of the GPER-1 receptor has been demonstrated through mechanisms such as apoptosis, cell cycle and arrest in G2 (85). Low levels of GPER-1 are associated with antitumor effects in prostate cancer (86). Interestingly, an overexpression of GPER-1 in ovarian cancer is associated with decreased tumor development (87).
Some research indicates that GPER-1 expression is strongly influenced by epigenetic factors, especially through DNA methylation. This process implies that proteins that bind methyl groups can recruit both activators and repressors, particularly on CpG islands, which are regions rich in cytosine and guanine dinucleotides. These islands are often found at transcription start sites (88). Two CpG islands are associated with GPER. One, located at approximately 1 kb upstream of the transcription initiation site, has been associated with the transcriptional regulation of GPER-1. Interestingly, breast cancer cell lines that express GPER-1 showed hypomethylation of this CpG island. Furthermore, treatment with 5-azacytidine, an inhibitor of DNA methyltransferases, increased GPER-1 expression (89). Suggesting an inverse relation between DNA methylation and GPER-1 expression in breast cancer (90). Similar results have been observed for gastric cancer (91) and colorectal cancer, with samples from patients showing higher methylation levels and lower GPER1 expression compared to patient-matched normal tissue (92). Recently, analysis of various databases has shown that DNA methylation of GPER-1 and ERα is associated with survival in tumor patients. It is suggested that methylation of these genes may play a role in cancer progression by modulating chromatin configuration (93).
Additionally, molecules that can mimic the biological effects of estrogens due to a structural homology with estradiol are globally cataloged as xenoestrogens. Environmental pollution determines our constant exposition to these molecules with estrogenic capacity. Raising interest in the association between xenoestrogens exposition and cancer development (94). Xenoestrogens are foreign to our physiology, some of these molecules have their origin in plants, as is the case of phytoestrogens, and others are of industrial origin, covering many molecules from phthalates to bisphenols (18). Much of the evidence indicates that industrial xenoestrogens may act as endocrine disruptors (18, 94, 95). In this context, bisphenol A (BPA) and phthalates, a chemical compound that is incorporated in plastic containers used to store water, beverages, food, and numerous items of modern life, stands out (96). Phthalates, BPA, and other types of bisphenols have been detected in virtually all biological fluids and tissues. These include amniotic fluid (97) and adipose tissue (98–100).
Phthalates, such as butylbenzyl phthalate (BBP), dibutyl phthalate (DBP) and di(2-ethylhexyl)phthalate (DEHP), have been shown to have estrogenic effects in breast cancer cells, interacting with estrogen receptor alpha (ERα) at micromolar concentrations (101, 102). Although their ability to induce cell proliferation suggests a possible interaction with GPER-1, direct binding between these phthalates and GPER-1 has not yet been demonstrated (102).
Environmentally relevant doses of BPA generate activation of classical estrogen receptors, inducing protumor activity (103). It has recently been proposed that stimulation of estradiol-sensitive breast cancer cells with BPA increases breast cancer cell proliferation (104). However, it has also been determined that BPA can exacerbate cancer cell behavior by acting on G protein-coupled receptors, specifically GPER-1 (13, 105) (Table 2).
Table 2. Factors contributing to breast cancer development.
The pathophysiological effects of different concentrations of BPA have been analyzed. High doses, in the micromole range, have been linked to oxidative stress, subcellular damage, cytotoxicity, and apoptosis (112). Chronic exposure to these high doses may facilitate inflammation, pancreatic beta-cell death and metabolic dysfunction (113, 114). However, low doses, in the nanomoles range, have raised more concern (115) due to their prevalence in the environment (116) and the variability of BPA in serum, ranging from 1 to 10 nM, which has a high potential to alter endocrine function (117). This alteration can interfere with the gonadotropin-releasing hormone (GnRH) release axis, generating alterations in early development and in the human reproductive cycle (118).
In murine models, low oral doses of BPA have shown remarkable proestrogenic activity (119). Several studies indicate that low concentrations of BPA can modify cell behavior in prostate (120) and mammary (121) tissues, which could increase long-term cancer risk. Additionally, exposure to BPA and other endocrine disruptors has adverse effects on genes that regulate placental function and fetal development (122, 123), associated with negative consequences on fetal development and neurological function (122).
Due to negative health effects and growing concern in the scientific community and the general public, the use of other bisphenols, such as bisphenol S (BPS) and bisphenol AF (BPAF), has been promoted (99). However, these compounds exhibit hormonal properties, with BPAF being more potent than BPS. In fact, several reports, using as models yeast (Saccharomyces cerevisiae), zebrafish (Danio rerio), or human and rat stem cells, indicate that their toxic and estrogenic effects are similar or even exceed those of BPA (106–108).
In MCF-7 cells, low concentrations of BPAF through GPER-1 triggered PI3K/Akt and ERK1/2 signaling pathways, promoting cell proliferation, and increased levels of intracellular calcium, and reactive oxygen species (ROS) (109). Recently, it has been observed in immortalized murine hypothalamic cells, both of embryonic and adult origin, that exposure to BPS, through GPER-1, induces the expression of the Agouti-related peptide (AgRP) gene, a neuropeptide crucial in the regulation of appetite and energy balance, which could contribute to metabolic disorders associated with obesity (124).
Adipose tissue tends to bioaccumulate various types of xenoestrogens, due to the lipophilic characteristics of these compounds (125, 126). This phenomenon, in the case of phthalates and bisphenols, has been consistently linked to adipogenesis, and to the long-term development of endocrine and metabolic diseases (127–129).
In perspective, exposure to hormone replacement therapy, contraceptive, or xenoestrogens triggers intracellular signaling pathways that are mediated by GPER-1 and induced by physiological estrogens (30). However, in the context of breast cancer, these pathways may exacerbate tumoral behavior, enhancing the signaling pathway activation or its components, such as ERK1/2, AKT, cyclic adenosine monophosphate (cAMP) or by increasing intracellular calcium levels. GPER-1 may also act through direct or indirect association with other estradiol-responsive receptors or inflammation-related receptors, and its levels may also be affected by the activity of cancer-associated fibroblasts (CAFs) in the tumor microenvironment (Figure 2). Thus, for example, continuous exposition to tamoxifen, the first-line drug against estradiol-sensitive breast cancer, overexpresses GPER-1, increasing calcium mobilization and cell proliferation (9). Suggesting that GPER-1 overexpression constitutes a mechanism of drug resistance (9, 110, 111).
Figure 2. GPER-1 plays a crucial role in the physiological regulation of the HPG axis. GPER-1 is involved in the intricate regulatory network of the hypothalamic-pituitary-gonadal (HPG) axis. The ubiquity of this receptor, both in the central nervous system and in peripheral tissues, determines an integrative role of neuroendocrine and environmental signals. In the hypothalamus and pituitary, GPER-1 modulates the synthesis and pulsatile release of gonadotropins, hormones essential for follicular development, ovulation and spermatogenesis. In the ovaries, GPER-1 mediates the effects of estradiol on cell proliferation, apoptosis and steroid synthesis, thus influencing ovarian function and fertility. The mammary gland, another target tissue of GPER-1, undergoes morphological and functional changes in response to hormonal fluctuations. Disruption of GPER-1 signaling by exposure to estrogenic chemicals or physiological alterations such as menopause can trigger a cascade of events leading to reproductive, metabolic and carcinogenic disorders.
Interestingly, a recognition domain of GPER-1 in ERα has recently been reported, such a region has also been found in a truncated isoform of estrogen receptor alpha, named as ERα36 (130). An association between GPER-1 and insulin-like growth factor (IGF1R) signaling, promoting breast cancer metastasis, has also been suggested (131). Similarly, a relationship of GPER-1 with proinflammatory receptors has been observed (9, 132). Further research is required to increase our understanding of the interactions between GPER-1 and other receptors, and the role those interactions play in breast cancer development.
GPER-1 expression has also been observed in triple-negative breast cancer (TNBC) (83), a neoplasm characterized by a lack of ERα, PR and HER2 receptors. In this context, GPER-1 can modulate key pathways, including MAPK activation and EGFR signaling (133), contributing to cell proliferation and invasion. This scenario associates TNBC with the most aggressive phenotypes of breast cancer (83). Indeed, the RAS/RAF/MEK/ERK signaling cascade, key in the physiological response to estradiol, has been found to be frequently over activated in various types of cancers, although mutations in this pathway are not usually described in breast cancer. TNBC cancer has been associated to driver mutations in the Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS), and v-Raf murine sarcoma viral oncogene homolog B (BRAF) genes, promoting the synthesis of K-RAS and RAF proteins (134). Furthermore, a recent report used CRISPR/Cas9 to knockout GPER-1 expression in triple-negative MDA- MB-231 cells. Cells lacking GPER-1 showed a shift towards pro-apoptotic and antiproliferative signaling driven by reduced cAMP levels and activation of the c-Jun N-terminal kinase (JNK/c- Jun)/p53/Noxa pathway (135). Therefore, GPER-1 would be intrinsically related to the mechanisms that determine the development of TNBC.
Additionally, in the tumor microenvironment, GPER-1 expression has been detected in CAFs. GPER-1 activation stimulates the secretion of proinflammatory factors such as interleukin 6 (IL-6) and epidermal growth factor (VEGF) (Figure 2). This phenomenon would ultimately also contribute to resistance to hormonal treatments such as tamoxifen (85).
Taken together, these data suggest that GPER-1 modulates a complex signaling network of importance for the development of estradiol-sensitive breast cancer and TNBC, which is influenced by several interrelated factors. First, GPER-1 expression and tumor cell type are critical, as GPER-1 shows remarkable versatility in the target signaling pathways it activates, which generates a variable impact depending on the cellular context. Second, the tumor microenvironment plays a crucial role; the extracellular matrix can modify GPER-1 activity and thus alter tumor responses. Third, activation of GPER-1 by molecules that mimic estrogen structure, such as xenoestrogens (e.g., Bisphenol A), poses a potential risk of endocrine disruption. Finally, the interaction of GPER-1 with other receptors, such as EGFR and ERα, may amplify estrogenic signaling, opening exciting opportunities to investigate combination therapies targeting these pathways.
4 Conclusion
The dynamic interaction between GPER-1 and signals from the hypothalamus-pituitary- gonads axis suggests a direct connection between sex hormone regulation and molecular events associated with the progression of several types of cancer, especially breast cancer. The ability of GPER-1 to modulate key signaling pathways, influence gene expression, and participate in specific molecular cascades in nervous and reproductive tissue is a developing area but represents a significant advance toward a greater understanding of the pathophysiology of breast cancer and other chronic nerve and metabolic diseases.
Recent discoveries about the interaction of GPER-1 with synthetic and environmental estrogens emphasize the importance of considering the expression and activity of this receptor in the formulation of more effective and specific therapeutic approaches for breast cancer, establishing an additional link that strengthens the ability to tailor therapeutic interventions to the specific molecular characteristics of each patient.
Author contributions
LMC: Writing – original draft, Writing – review & editing, Conceptualization. YA: Writing – review & editing. MO: Writing – review & editing. SD: Writing – review & editing. RT: Writing – review & editing, Conceptualization.
Funding
The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by ANID FONDECYT INICIACIÓN 11240855 (LMC), ANID FONDECYT INICIACIÓN 11230898 (RT) and ANID FONDECYT POSTDOCTORADO 3200655 (YA), and the Vicerrectoría de Investigación y Doctorados (VRID), Universidad San Sebastián, for grant USS-FIN-23-DOCI-06 (LMC).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Keywords: GPER-1, estrogen, hypothalamic-pituitary-gonadal axis, breast cancer, endocrine resistance, personalized medicine
Citation: Molina Calistro L, Arancibia Y, Olivera MA, Domke S and Torres RF (2025) Interaction of GPER-1 with the endocrine signaling axis in breast cancer. Front. Endocrinol. 16:1494411. doi: 10.3389/fendo.2025.1494411
Received: 10 September 2024; Accepted: 06 January 2025;
Published: 24 January 2025.
Edited by:
Ignacio Camacho-Arroyo, National Autonomous University of Mexico, MexicoReviewed by:
Mauricio Rodriguez-Dorantes, National Institute of Genomic Medicine (INMEGEN), MexicoRocío García-Becerra, National Autonomous University of Mexico, Mexico
Copyright © 2025 Molina Calistro, Arancibia, Olivera, Domke and Torres. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Luis Molina Calistro, bHVpcy5tb2xpbmFAdXNzLmNs; Rodrigo Flavio Torres, cm9kcmlnby50b3JyZXNAdXNzLmNs