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<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Cell Dev. Biol.</journal-id>
<journal-title>Frontiers in Cell and Developmental Biology</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Cell Dev. Biol.</abbrev-journal-title>
<issn pub-type="epub">2296-634X</issn>
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<publisher-name>Frontiers Media S.A.</publisher-name>
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<article-id pub-id-type="publisher-id">1338448</article-id>
<article-id pub-id-type="doi">10.3389/fcell.2024.1338448</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Cell and Developmental Biology</subject>
<subj-group>
<subject>Review</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Current progress and prospects for G protein-coupled estrogen receptor in triple-negative breast cancer</article-title>
<alt-title alt-title-type="left-running-head">Zhang et al.</alt-title>
<alt-title alt-title-type="right-running-head">
<ext-link ext-link-type="uri" xlink:href="https://doi.org/10.3389/fcell.2024.1338448">10.3389/fcell.2024.1338448</ext-link>
</alt-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Zhang</surname>
<given-names>Duo</given-names>
</name>
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</contrib>
<contrib contrib-type="author">
<name>
<surname>Chen</surname>
<given-names>Hong</given-names>
</name>
<role content-type="https://credit.niso.org/contributor-roles/supervision/"/>
<role content-type="https://credit.niso.org/contributor-roles/validation/"/>
<role content-type="https://credit.niso.org/contributor-roles/Writing - review &#x26; editing/"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Wang</surname>
<given-names>Jinpeng</given-names>
</name>
<role content-type="https://credit.niso.org/contributor-roles/supervision/"/>
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</contrib>
<contrib contrib-type="author">
<name>
<surname>Ji</surname>
<given-names>Jiale</given-names>
</name>
<role content-type="https://credit.niso.org/contributor-roles/supervision/"/>
<role content-type="https://credit.niso.org/contributor-roles/validation/"/>
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</contrib>
<contrib contrib-type="author">
<name>
<surname>Imam</surname>
<given-names>Murshid</given-names>
</name>
<uri xlink:href="https://loop.frontiersin.org/people/2255831/overview"/>
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</contrib>
<contrib contrib-type="author">
<name>
<surname>Zhang</surname>
<given-names>Zhijie</given-names>
</name>
<role content-type="https://credit.niso.org/contributor-roles/supervision/"/>
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</contrib>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Yan</surname>
<given-names>Shunchao</given-names>
</name>
<xref ref-type="corresp" rid="c001">&#x2a;</xref>
<uri xlink:href="https://loop.frontiersin.org/people/1511206/overview"/>
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</contrib-group>
<aff>
<institution>Department of Oncology</institution>, <institution>Shengjing Hospital of China Medical University</institution>, <addr-line>Shenyang</addr-line>, <country>China</country>
</aff>
<author-notes>
<fn fn-type="edited-by">
<p>
<bold>Edited by:</bold> <ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/1354078/overview">Weipeng Zhao</ext-link>, Tianjin Medical University Cancer Institute and Hospital, China</p>
</fn>
<fn fn-type="edited-by">
<p>
<bold>Reviewed by:</bold> <ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/1835702/overview">Jia Li</ext-link>, University of North Carolina at Charlotte, United States</p>
<p>
<ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/125502/overview">Guan Chen</ext-link>, Medical College of Wisconsin, United States</p>
</fn>
<corresp id="c001">&#x2a;Correspondence: Shunchao Yan, <email>yansc@cmu.edu.cn</email>
</corresp>
</author-notes>
<pub-date pub-type="epub">
<day>27</day>
<month>02</month>
<year>2024</year>
</pub-date>
<pub-date pub-type="collection">
<year>2024</year>
</pub-date>
<volume>12</volume>
<elocation-id>1338448</elocation-id>
<history>
<date date-type="received">
<day>23</day>
<month>11</month>
<year>2023</year>
</date>
<date date-type="accepted">
<day>08</day>
<month>02</month>
<year>2024</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#xa9; 2024 Zhang, Chen, Wang, Ji, Imam, Zhang and Yan.</copyright-statement>
<copyright-year>2024</copyright-year>
<copyright-holder>Zhang, Chen, Wang, Ji, Imam, Zhang and Yan</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<p>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.</p>
</license>
</permissions>
<abstract>
<p>Triple-negative breast cancer (TNBC) is a biologically and clinically heterogeneous disease. The G protein-coupled estrogen receptor (GPER) plays a crucial role in mediating the effect of estrogen and estrogen-like compounds in TNBC cells. Compared with other subtypes, GPER has a higher expression in TNBC. The GPER mechanisms have been thoroughly characterized and analyzed in estrogen receptor &#x3b1; (ER&#x3b1;) positive breast cancer, but not in TNBC. Our previous work revealed that a higher expression of GPER mRNA indicates a better prognosis for ER&#x3b1;-positive breast cancer; however, its effects in TNBC differ. Whether GPER could serve as a predictive prognostic marker or therapeutic target for TNBC remains unclear. In this review, we provide a detailed introduction to the subcellular localization of GPER, the different effects of various ligands, and the interactions between GPER and closely associated factors in TNBC. We focused on the internal molecular mechanisms specific to TNBC and thoroughly explored the role of GPER in promoting tumor development. We also discussed the interaction of GPER with specific cytokines and chemokines, and the relationship between GPER and immune evasion. Additionally, we discussed the feasibility of using GPER as a therapeutic target in the context of existing studies. This comprehensive review highlights the effects of GPER on TNBC, providing a framework and directions for future research.</p>
</abstract>
<kwd-group>
<kwd>G protein-coupled estrogen receptor</kwd>
<kwd>triple-negative breast cancer</kwd>
<kwd>tumor development</kwd>
<kwd>mechanism</kwd>
<kwd>prognostic</kwd>
</kwd-group>
<contract-num rid="cn001">21-173-9-69</contract-num>
<contract-num rid="cn002">2022JH2/101500066</contract-num>
<contract-sponsor id="cn001">Shenyang Municipal Bureau of Science and Technology<named-content content-type="fundref-id">10.13039/501100007765</named-content>
</contract-sponsor>
<contract-sponsor id="cn002">Department of Science and Technology of Liaoning Province<named-content content-type="fundref-id">10.13039/501100012131</named-content>
</contract-sponsor>
<contract-sponsor id="cn003">Shengjing Hospital<named-content content-type="fundref-id">10.13039/501100015226</named-content>
</contract-sponsor>
<custom-meta-wrap>
<custom-meta>
<meta-name>section-at-acceptance</meta-name>
<meta-value>Cancer Cell Biology</meta-value>
</custom-meta>
</custom-meta-wrap>
</article-meta>
</front>
<body>
<sec sec-type="intro" id="s1">
<title>1 Introduction</title>
<p>According to the International Agency for Research on Cancers GLOBOCAN, global cancer burden data demonstrate that breast cancer has emerged as the most commonly diagnosed cancer, accounting for roughly 2.3 million (11.7%) new cases in 2020 (<xref ref-type="bibr" rid="B159">Sung et al., 2021</xref>; <xref ref-type="bibr" rid="B31">Chhikara and Parang, 2023</xref>). Breast cancer is the primary reason for cancer-related mortality among women worldwide (<xref ref-type="bibr" rid="B18">Cao et al., 2021</xref>). Triple-negative breast cancer (TNBC) accounts for approximately 15% of all breast cancer cases and &#x3e;50% of breast cancer-related deaths (<xref ref-type="bibr" rid="B120">Morris et al., 2007</xref>). This subtype of breast cancer is particularly aggressive and lacks estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2).</p>
<p>TNBC demonstrates heterogeneity in both genetic expression and biological behavior, thereby contributing to its poor prognosis. Numerous studies have prioritized the accurate classification of TNBC to identify targeted treatments. <xref ref-type="bibr" rid="B95">Lehmann et al. (2011)</xref> identified seven subtypes of TNBC cell lines: luminal androgen receptor, immunomodulatory, mesenchymal stem-like, basal-like 1, basal-like 2, mesenchymal, and unstable. Moreover, <xref ref-type="bibr" rid="B35">Dai et al. (2017)</xref> proposed that TNBC cell lines can be divided into two distinct subtypes based on a diverse range of genetic expressions. The first subtype, triple-negative A, is characterized by an enrichment of basal markers, whereas triple-negative B is defined by a gene expression profile that indicates an increased potential for tumor invasiveness. This classification system assists in identifying high-risk individuals among patients with TNBC. Furthermore, <xref ref-type="bibr" rid="B79">Jiang et al. (2019)</xref> outlined a multi-omics landscape of TNBC, leading to the categorization of TNBC into four subtypes: immunomodulatory, basal-like immune-suppressed, luminal androgen receptor, and mesenchymal-like. This approach identified potential therapeutic targets for each subtype and optimized the precision treatment strategy for TNBC (<xref ref-type="bibr" rid="B79">Jiang et al., 2019</xref>). TNBC is resistant to specific hormone therapies and presents limited treatment options compared with those of other breast cancer types. To date, chemotherapy has been the primary approach for improving outcomes for patients with TNBC. Although new therapies such as poly (ADP-ribose) polymerase inhibitors and immunotherapy have been formulated in recent years, the TNBC prognosis remains poor due to heterogeneity (<xref ref-type="bibr" rid="B60">Garc&#xed;a Fern&#xe1;ndez et al., 2012</xref>; <xref ref-type="bibr" rid="B101">Li et al., 2017</xref>; <xref ref-type="bibr" rid="B152">Sharma, 2018</xref>; <xref ref-type="bibr" rid="B68">He et al., 2020</xref>; <xref ref-type="bibr" rid="B192">Yin L. et al., 2020</xref>). Therefore, identifying the molecular biological factors that impact or predict TNBC prognosis, exploring their mechanisms of action, and developing effective targeted therapeutic drugs with few side effects are crucial.</p>
<p>The lack of a response to hormones is regarded as an essential feature of TNBC. Nevertheless, researchers have observed the expression of certain non-classical steroid endocrine receptors in TNBC, in addition to classical ER. The G protein-coupled estrogen receptor (GPER), serving as a non-nuclear receptor, signifies the biological and clinical significance of steroid hormones in TNBC. Notably, GPER exhibits a higher expression level in TNBC than in other subtypes (<xref ref-type="bibr" rid="B157">Steiman et al., 2013</xref>). Existing research is controversial, with some studies indicating that GPER has a tumor-promoting effect in TNBC and is associated with increased recurrence rates, whereas others indicate the protective anti-tumor effect of GPER (<xref ref-type="bibr" rid="B195">Yu et al., 2014</xref>; <xref ref-type="bibr" rid="B72">Hern&#xe1;ndez-Silva et al., 2020</xref>). Therefore, a comprehensive perspective is required. In this review, we summarized the effects of GPER on TNBC from the perspective of signaling pathways and related mechanisms of action. Moreover, we have explored the potential of GPER as a prospective therapeutic target for TNBC based on existing original research.</p>
</sec>
<sec id="s2">
<title>2 G protein-coupled estrogen receptor</title>
<sec id="s2-1">
<title>2.1 Discovery of GPER in breast cancer</title>
<p>Since the 1960s, researchers have observed that the uterine adenyl cyclase system and intracellular calcium have an instantaneous ability to react with estrogen in ovariectomized rats, which initiates cyclic adenosine monophosphate (cAMP) formation and induces calcium mobilization (<xref ref-type="bibr" rid="B160">Szego and Davis, 1967</xref>; <xref ref-type="bibr" rid="B128">Pietras and Szego, 1975</xref>). These effects are referred to as extranuclear, non-genomic effects (<xref ref-type="bibr" rid="B109">Luo and Liu, 2020</xref>). Thereafter, <xref ref-type="bibr" rid="B4">Aronica et al. (1994)</xref> demonstrated that estrogen increases adenylate cyclase activity, leading to increased cAMP production in human MCF-7 cells. At this time, researchers were not aware that GPER, but not just ER&#x3b1; played a key role in this effect (<xref ref-type="bibr" rid="B4">Aronica et al., 1994</xref>). Subsequently, the GPR30 gene was identified as a gene homologous to the G protein-coupled receptor (GPCR) family in breast cancer (<xref ref-type="bibr" rid="B19">Carmeci et al., 1997</xref>; <xref ref-type="bibr" rid="B98">Levoye et al., 2006</xref>). Moreover, <xref ref-type="bibr" rid="B51">Filardo et al. (2000)</xref> found that the rapid activation of extracellular signal-regulated kinases (ERK) by 17&#x3b2;-estradiol (E2) requires the participation of an orphan GPCR, with seven transmembrane domains. <xref ref-type="bibr" rid="B113">Maggiolini et al. (2004)</xref> demonstrated the ability of E2 to stimulate c-Fos gene expression in both ER&#x3b1;-positive MCF-7 and ER&#x3b1;-negative SKBR3 human breast cancer cells. This effect occurred through two different pathways: one involving the ER&#x3b1; and the other through the GPCR homolog GPER, independent of the ER&#x3b1; (<xref ref-type="bibr" rid="B113">Maggiolini et al., 2004</xref>). <xref ref-type="bibr" rid="B139">Revankar et al. (2005)</xref> eventually established GPER as a distinct ER&#x3b1; in SKBR3 cells, with a signaling pathway different from ER&#x3b1;-mediated signaling. Additionally, they observed E2 as the natural ligand for GPER and found that the effects of estrogen on this receptor were likely influenced by its intracellular localization. Subsequently, specific agonists (G-1) and antagonists (G-15 and G-36) targeting GPER were sequentially developed. With the deepening of our understanding of TNBC, studies on the involvement of GPER in TNBC have gradually increased. Since 2012, attention has been focused on the relationship between GPER activation and clinical pathological characteristics in TNBC. Numerous studies have focused on further investigating the mechanisms of GPER action in estrogen signaling and its implications for the development and progression of TNBC. The exploration of GPER in breast cancer is summarized in the form of a timeline in <xref ref-type="fig" rid="F1">Figure 1A</xref>.</p>
<fig id="F1" position="float">
<label>FIGURE 1</label>
<caption>
<p>
<bold>(A)</bold> Timeline of G protein-coupled estrogen receptor (GPER) exploration in breast cancer. <bold>(B)</bold> GPER protein is predominantly localized to the plasma membranes with seven transmembrane domains, ligand binding, and G protein binding pockets. Estrogen/agonist binding to GPER activates a stimulatory G protein &#x3b1;-subunit (G&#x3b1;<italic>
<sub>s</sub>
</italic>) and results in GPER stimulation. Antagonist binding to GPER leads to an inhibitory G protein &#x3b1;-subunit (G&#x3b1;<italic>
<sub>i</sub>
</italic>) and inactivated GPER. <bold>(C)</bold> GPER&#x2019;s diverse functions include regulation of cell proliferation, invasion, metastasis, and angiogenesis, modulation of cancer-associated fibroblasts (CAFs), control of tumor stem cell functionality, cytokine production, and secretion, and evasion of immune responses. Abbreviations: GPER, G protein-coupled estrogen receptor; BC, breast cancer; TNBC, Triple-negative breast cancer; CAF, cancer-associated fibroblasts.</p>
</caption>
<graphic xlink:href="fcell-12-1338448-g001.tif"/>
</fig>
</sec>
<sec id="s2-2">
<title>2.2 Subcellular localization of GPER</title>
<p>As a seven-transmembrane G protein-coupled receptor, GPER is typically assumed to be located on the plasma membrane, similar to most GPCRs (<xref ref-type="bibr" rid="B165">Thomas et al., 2005</xref>). While GPER is concentrated in the plasma membranes of certain tissues, its intracellular detection has also been reported (<xref ref-type="bibr" rid="B49">Filardo et al., 2007</xref>). Furthermore, the distribution of GPER varies across species, tissues, and cell types. Initially, <xref ref-type="bibr" rid="B57">Funakoshi et al. (2006)</xref> observed that GPER was localized in the plasma membrane of pyramidal neurons in the hippocampal CA2 area of the rat brain. Moreover, upon agonist stimulation, the GPER-transfected HeLa cells exhibited translocation of the receptor from the plasma membrane to the cytoplasm (<xref ref-type="bibr" rid="B57">Funakoshi et al., 2006</xref>). Additionally, GPER is primarily located in the plasma membrane of the uterine epithelia, myometrium, and renal epithelia (<xref ref-type="bibr" rid="B29">Cheng et al., 2011a</xref>; <xref ref-type="bibr" rid="B59">Gao et al., 2011</xref>; <xref ref-type="bibr" rid="B103">Lindsey et al., 2011</xref>; <xref ref-type="bibr" rid="B114">Maiti et al., 2011</xref>). However, a significant proportion of GPER is localized within the intracellular structure. <xref ref-type="bibr" rid="B139">Revankar et al. (2005)</xref> conducted a study using fluorescent E2 derivatives (E2-Alexas) to examine the localization features of GPER in monkey kidney fibroblasts. Interestingly, they observed that E2-Alexas did not effectively label the plasma membrane. Instead, it is primarily bound to the endoplasmic reticulum. Furthermore, staining with E2-Alexas or antibodies also revealed colocalization in the Golgi apparatus and nuclear membrane of GPER (<xref ref-type="bibr" rid="B139">Revankar et al., 2005</xref>). Similarly, in a study by <xref ref-type="bibr" rid="B12">Brailoiu et al. (2007)</xref>, GPER was observed to be distributed within the neuronal cytoplasm using immunohistochemical analysis.</p>
<p>GPER primarily exhibits a cytoplasmic staining pattern in breast carcinoma tissues, with minimal presence on the cell surface (<xref ref-type="bibr" rid="B165">Thomas et al., 2005</xref>; <xref ref-type="bibr" rid="B50">Filardo et al., 2006</xref>; <xref ref-type="bibr" rid="B106">Luo et al., 2011</xref>). Interestingly, a fraction of tumor specimens exhibited both nuclear and cytoplasmic staining (<xref ref-type="bibr" rid="B76">Ignatov et al., 2011</xref>; <xref ref-type="bibr" rid="B147">Samartzis et al., 2014</xref>). The differential subcellular localization of GPER may be explained by a dynamic change mechanism (<xref ref-type="bibr" rid="B30">Cheng et al., 2011b</xref>). Under ligand-independent conditions, GPER employs an endocytic trafficking mechanism through clathrin-coated vesicles, accumulates in the perinuclear compartment, and is dispersed in the cytoplasm (<xref ref-type="bibr" rid="B30">Cheng et al., 2011b</xref>). Based on this evidence, we speculated that the different staining patterns may reflect the dynamic and time-dependent intracellular trafficking process of GPER. The action of GPER may be regulated by the amount of receptors present at different subcellular locations.</p>
<p>Differences in subcellular localization may have distinct biological implications for different breast carcinoma subtypes. <xref ref-type="bibr" rid="B50">Filardo et al. (2006)</xref> observed that the cytoplasmic staining of GPER in breast tumor tissue was nearly two-fold higher than that in tumors without GPER expression. Moreover, <xref ref-type="bibr" rid="B156">Sj&#xf6;str&#xf6;m et al. (2014)</xref> conducted a study to identify whether the subcellular localization of GPER could be an independent prognostic factor and revealed a positive correlation between the overexpression of plasma membrane GPER and a high histological grade. Therefore, plasma membrane localization of GPER may be a critical event that suggests a poor prognosis for breast cancer (<xref ref-type="bibr" rid="B156">Sj&#xf6;str&#xf6;m et al., 2014</xref>). <xref ref-type="bibr" rid="B147">Samartzis et al. (2014)</xref> observed a substantial correlation between the presence of cytoplasmic GPER and low tumor stage, luminal subtypes, and improved histological differentiation. In contrast, the expression of nuclear GPER is strongly associated with the triple-negative subtype and poorly differentiated tumors (<xref ref-type="bibr" rid="B147">Samartzis et al., 2014</xref>). Consistent results have been reported in our meta-analysis, where high GPER cytoplasmic expression, but not nuclear expression, is associated with improved outcomes in ER&#x03b1;-positive breast cancer (<xref ref-type="bibr" rid="B197">Zhang et al., 2022</xref>). As an understudied and important potential next frontier, whether the subcellular location of GPER in breast cancer has distinct prognostic implications needs further investigation.</p>
</sec>
<sec id="s2-3">
<title>2.3 GPER ligands</title>
<p>
<xref ref-type="bibr" rid="B139">Revankar et al. (2005)</xref> found that the natural hormone E2 is a paramount ligand of GPER (<xref ref-type="bibr" rid="B165">Thomas et al., 2005</xref>). Estriol (E3), an E2-based steroid, has been identified as a GPER antagonist, and estrone has been described as an agonist for GPER (<xref ref-type="bibr" rid="B90">Lappano et al., 2010</xref>). GPER exhibits a higher binding affinity to E2 than that of estrone and estriol (<xref ref-type="bibr" rid="B139">Revankar et al., 2005</xref>). The abundant cholesterol metabolite 27-hydroxycholesterol is a novel ligand for GPER, and its signaling axis plays a crucial role in ER&#x03b1;-negative breast cancer progression (<xref ref-type="bibr" rid="B5">Avena et al., 2022</xref>).</p>
<p>In 2006, researchers synthesized G-1, the first selective agonist for GPER (<xref ref-type="bibr" rid="B11">Bologa et al., 2006</xref>). Subsequent studies revealed a binding affinity of 10&#xa0;nM between G-1 and GPER. In 2009, a selective antagonist of GPER, referred to as G-15, was shown to inhibit the calcium mobilizing effect of E2 in the SKBR3 cell line (<xref ref-type="bibr" rid="B42">Dennis et al., 2009</xref>). After 2&#xa0;years, another GPER antagonist, G-36, was synthesized. This compound had a high affinity for GPER and a weak cross-reactivity with ER&#x3b1; (<xref ref-type="bibr" rid="B43">Dennis et al., 2011</xref>). Furthermore, <xref ref-type="bibr" rid="B91">Lappano et al. (2012)</xref> investigated two additional molecules, GPER-L1 and GPER-L2, which function as specific agonists of GPER, activating downstream signaling pathways.</p>
<p>Tamoxifen is the first accredited selective ER&#x03b1; modulator for breast cancer therapy and has demonstrated efficacy in reducing recurrence rates and improving the prognosis of ER&#x03b1;-positive breast tumors (<xref ref-type="bibr" rid="B3">Ariazi et al., 2006</xref>; <xref ref-type="bibr" rid="B45">Early Breast Cancer Trialists&#x2019; Collaborative Group, 2011</xref>). Tamoxifen acts as a GPER agonist, induces aromatase expression, and contributes to resistance to endocrine therapy in breast cancer (<xref ref-type="bibr" rid="B117">Meijer et al., 2006</xref>; <xref ref-type="bibr" rid="B168">van Agthoven et al., 2009</xref>; <xref ref-type="bibr" rid="B76">Ignatov et al., 2011</xref>; <xref ref-type="bibr" rid="B23">Catalano et al., 2014</xref>; <xref ref-type="bibr" rid="B190">Yin et al., 2017</xref>; <xref ref-type="bibr" rid="B119">Molina et al., 2020</xref>; <xref ref-type="bibr" rid="B194">Yu et al., 2020</xref>). Similarly, as a selective ER&#x03b1; downregulator, ICI182,780 (fulvestrant) displays significant binding to GPER and activates GPER in breast cancer (<xref ref-type="bibr" rid="B125">Osborne et al., 2004</xref>; <xref ref-type="bibr" rid="B165">Thomas et al., 2005</xref>).</p>
<p>Several plant-derived natural phytoestrogens have been shown to bind and/or activate ER&#x03b1; and other ERs (specifically GPER), such as daidzein (<xref ref-type="bibr" rid="B82">Kajta et al., 2013</xref>), genistein (<xref ref-type="bibr" rid="B164">Thomas and Dong, 2006</xref>; <xref ref-type="bibr" rid="B170">Vivacqua et al., 2006</xref>), resveratrol (<xref ref-type="bibr" rid="B44">Dong et al., 2013</xref>), and quercetin (<xref ref-type="bibr" rid="B113">Maggiolini et al., 2004</xref>). In addition, numerous xenoestrogens have been recognized as GPER ligands, including dichlorodiphenyltrichloroethane (<xref ref-type="bibr" rid="B81">Kajta et al., 2014</xref>), methoxychlor, atrazine (<xref ref-type="bibr" rid="B164">Thomas and Dong, 2006</xref>), bisphenol A (BPA) (<xref ref-type="bibr" rid="B198">Zhang et al., 2016</xref>), and bisphenol S (BPS) (<xref ref-type="bibr" rid="B41">Deng et al., 2018</xref>). The significance of BPA and BPS actions on GPER in the growth and migration of TNBC cells has been revealed. BPA is an industrially synthesized chemical compound with endocrine-disrupting effects that promote the growth of rat mammary tumor cells (<xref ref-type="bibr" rid="B169">Vandenberg et al., 2008</xref>; <xref ref-type="bibr" rid="B175">Wang et al., 2014</xref>; <xref ref-type="bibr" rid="B198">Zhang et al., 2016</xref>). In TNBC, BPA activates the focal adhesion kinase (FAK)/steroid receptor coactivator (SRC)/ERK signaling pathway and focal adhesion assembly by activating GPER and inducing epidermal growth factor receptor (EGFR) transactivation (<xref ref-type="bibr" rid="B20">Castillo Sanchez et al., 2016</xref>; <xref ref-type="bibr" rid="B21">Castillo-Sanchez et al., 2020</xref>). Tetrachlorobisphenol A (TCBPA) is a chlorinated derivative of BPA and exhibits estrogenic activity. Low TCBPA concentrations regulate the expression of GPER and its downstream target genes, resulting in the proliferation of TNBC cells (<xref ref-type="bibr" rid="B96">Lei et al., 2021</xref>). In comparison to BPA, BPS exhibits greater stability while exhibiting strong estrogenic responses. BPS was found to facilitate TNBC cell metastasis through the GPER/Hippo-Yes-associated protein 1 pathway (<xref ref-type="bibr" rid="B200">Zhao et al., 2008</xref>; <xref ref-type="bibr" rid="B58">Furth and Aylon, 2017</xref>), but it does not affect tumor proliferation (<xref ref-type="bibr" rid="B41">Deng et al., 2018</xref>). <xref ref-type="bibr" rid="B41">Deng et al. (2018)</xref> suggested that the reduced stimulation of proliferation by BPS in their study may be attributed to differences in cell lines or ER&#x3b1;/&#x3b2; expression status. Altogether, the positive and negative inhibitory effects of these GPER ligands provide a foundation for further exploration (<xref ref-type="table" rid="T1">Table 1</xref>).</p>
<table-wrap id="T1" position="float">
<label>TABLE 1</label>
<caption>
<p>Mechanisms of GPER agonists and antagonists in breast cancer.</p>
</caption>
<table>
<thead valign="top">
<tr>
<th align="left">Name</th>
<th align="left">Mechanism</th>
<th align="left">Experiment cell lines</th>
<th align="left">Specificity for GPER</th>
<th align="left">References</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td colspan="5" align="left">Agonist</td>
</tr>
<tr>
<td align="left">G-1</td>
<td align="left">Binds specifically to GPER and activates the GPER/EGFR/ERK signaling pathway</td>
<td align="left">HCC 1806, HCC70, MDA-MB-453, SKBR3</td>
<td align="left">Specific</td>
<td align="left">
<xref ref-type="bibr" rid="B11">Bologa et al. (2006)</xref>
</td>
</tr>
<tr>
<td rowspan="2" align="left">17&#x3b2;-estradiol (E2)</td>
<td rowspan="2" align="left">Binds to GPER and induces rapid activation of the GPER/EGFR/ERK signaling pathway, which promotes breast cancer cell growth and invasion</td>
<td align="left">MCF-7, SKBR3</td>
<td rowspan="2" align="left">Non-specific</td>
<td rowspan="2" align="left">
<xref ref-type="bibr" rid="B195">Yu et al. (2014)</xref>
</td>
</tr>
<tr>
<td align="left">MDA-MB-468, MDA-MB-231, MDA-MB-436</td>
</tr>
<tr>
<td align="left">GPER-L1</td>
<td rowspan="2" align="left">Binds specifically to GPER, thereby upregulating GPER target genes and inducing breast cancer cell proliferation</td>
<td rowspan="2" align="left">SKBR3</td>
<td rowspan="2" align="left">Specific</td>
<td rowspan="2" align="left">
<xref ref-type="bibr" rid="B91">Lappano et al. (2012)</xref>
</td>
</tr>
<tr>
<td align="left">GPER-L2</td>
</tr>
<tr>
<td align="left">Tamoxifen</td>
<td align="left">Binds to GPER, upregulates GPER expression, and promotes breast cancer cell proliferation, resulting in endocrine resistance</td>
<td align="left">MCF-7, SKBR3</td>
<td align="left">Non-specific</td>
<td align="left">
<xref ref-type="bibr" rid="B23">Catalano et al. (2014)</xref>
</td>
</tr>
<tr>
<td align="left">27-hydroxycholesterol</td>
<td align="left">Binds to GPER and mediates the activation of ERK1/2 and NF-&#x3ba;B, thereby increasing tumor proliferation</td>
<td align="left">MDA-MB-231, MDA-MB-468</td>
<td align="left">Non-specific</td>
<td align="left">
<xref ref-type="bibr" rid="B5">Avena et al. (2022)</xref>
</td>
</tr>
<tr>
<td align="left">ICI182,780 (fulvestrant)</td>
<td align="left">Activates the ERK and PI3K pathway through binding to GPER, resulting in endocrine resistance</td>
<td align="left">MCF-7</td>
<td align="left">Non-specific</td>
<td align="left">
<xref ref-type="bibr" rid="B125">Osborne et al. (2004)</xref>
</td>
</tr>
<tr>
<td align="left">Bisphenol A (BPA)</td>
<td align="left">BPA activates GPER and stimulates the FAK/SRC/ERK and EGFR signaling pathway and mediates breast cancer cell migration</td>
<td align="left">MDA-MB-231</td>
<td align="left">Non-specific</td>
<td align="left">
<xref ref-type="bibr" rid="B21">Castillo-Sanchez et al. (2020)</xref>
</td>
</tr>
<tr>
<td align="left">tetrachlorobisphenol A (TCBPA)</td>
<td align="left">TCBPA upregulates GPER expression and mediates ERK and Akt signaling, resulting in breast cancer cells proliferation</td>
<td align="left">MCF-7, SKBR3, MDA-MB-231 cells</td>
<td align="left">Non-specific</td>
<td align="left">
<xref ref-type="bibr" rid="B96">Lei et al. (2021)</xref>
</td>
</tr>
<tr>
<td align="left">Bisphenol S (BPS)</td>
<td align="left">BPS facilitates TNBC cell metastasis through the GPER/Hippo-YAP pathway</td>
<td align="left">MDA-MB-231, BT-549 cells</td>
<td align="left">Non-specific</td>
<td align="left">
<xref ref-type="bibr" rid="B41">Deng et al. (2018)</xref>
</td>
</tr>
<tr>
<td align="left">Berberine (BBR)</td>
<td align="left">Promotes the transcription of GPER and inhibits the viability and migration of cells</td>
<td align="left">MDA-MB-231, MDA-MB-436, MDA-MB-468</td>
<td align="left">Non-specific</td>
<td align="left">
<xref ref-type="bibr" rid="B136">Qi et al. (2021)</xref>
</td>
</tr>
<tr>
<td align="left">Chrysin-nanoparticles (NP)</td>
<td align="left">NPs inhibit proliferation and migration of TNBC via activation of GPER and suppress PI3K, p-JNK, and NF-&#x3ba;B expression</td>
<td align="left">MDA-MB-231</td>
<td align="left">Non-specific</td>
<td align="left">
<xref ref-type="bibr" rid="B84">Kim and Jung (2020)</xref>
</td>
</tr>
<tr>
<td align="left">Tanshinone IIA</td>
<td align="left">Binds to GPER and induces apoptosis in TNBC cells and inhibits migration via the GPER/EGFR/ERK signaling pathway</td>
<td align="left">MDA-MB-231</td>
<td align="left">Non-specific</td>
<td align="left">
<xref ref-type="bibr" rid="B69">He et al. (2023)</xref>
</td>
</tr>
<tr>
<td colspan="5" align="left">Antagonist</td>
</tr>
<tr>
<td align="left">G-15</td>
<td align="left">Inhibits GPER-dependent E2 signaling</td>
<td align="left">HCC 1806, HCC70</td>
<td align="left">Specific</td>
<td align="left">
<xref ref-type="bibr" rid="B42">Dennis et al. (2009)</xref>
</td>
</tr>
<tr>
<td align="left">G-36</td>
<td align="left">Inhibits GPER-dependent E2 signaling</td>
<td align="left">SKBR3</td>
<td align="left">Specific</td>
<td align="left">
<xref ref-type="bibr" rid="B43">Dennis et al. (2011)</xref>
</td>
</tr>
<tr>
<td align="left">Estriol (E3)</td>
<td align="left">Inhibits the GPER/EGFR/ERK signaling pathway and breast cancer cell proliferation</td>
<td align="left">SKBR3</td>
<td align="left">Non-specific</td>
<td align="left">
<xref ref-type="bibr" rid="B90">Lappano et al. (2010)</xref>
</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn>
<p>Abbreviations: GPER, G-protein-coupled Estrogen Receptor; E2, estrogen; ERK, extracellular signal-regulated kinase; EGFR, epidermal growth factor receptor; FAK, focal adhesion kinase; SRC, steroid receptor coactivator; Akt, protein kinase B; TNBC, triple-negative breast cancer; YAP, Yes-associated protein 1; PI3K, phosphoinositide 3-kinase; JNK, c-Jun N-terminal kinase; NF-&#x3ba;B, nuclear factor kappa B.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</sec>
<sec id="s2-4">
<title>2.4 Role of GPER in TNBC</title>
<p>In normal breast tissues, GPER is moderately expressed (<xref ref-type="bibr" rid="B166">Uhl&#xe9;n et al., 2015</xref>) and has been detected in diverse cancer cell lines and malignant tumors, such as endometrial carcinoma (<xref ref-type="bibr" rid="B70">He et al., 2009</xref>), ovarian cancer (<xref ref-type="bibr" rid="B1">Albanito et al., 2007</xref>), melanoma (<xref ref-type="bibr" rid="B47">F&#xe1;bi&#xe1;n et al., 2017</xref>), prostate cancer (<xref ref-type="bibr" rid="B25">Chan et al., 2010</xref>), thyroid cancer (<xref ref-type="bibr" rid="B170">Vivacqua et al., 2006</xref>), and testicular germ cell tumors (<xref ref-type="bibr" rid="B55">Franco et al., 2011</xref>). In invasive breast cancer, GPER exhibits a positivity rate estimated between 50% and 60%, as evidenced by immunohistochemistry (<xref ref-type="bibr" rid="B50">Filardo et al., 2006</xref>; <xref ref-type="bibr" rid="B76">Ignatov et al., 2011</xref>; <xref ref-type="bibr" rid="B157">Steiman et al., 2013</xref>). The expression of GPER varies among different ER&#x3b1;-positive breast cancer cell lines. In T47D cell lines, GPER is predominantly expressed at elevated levels in the cytoplasm, whereas in MCF-7 cells, GPER expression is primarily detected in the nucleus and is low (<xref ref-type="bibr" rid="B147">Samartzis et al., 2014</xref>). Moreover, within a cohort of ER&#x3b1;-negative breast cancer, the positivity rate of GPER exceeds 60% (<xref ref-type="bibr" rid="B106">Luo et al., 2011</xref>). Furthermore, in TNBC, GPER is frequently overexpressed, with rates reaching as high as 68.8% (<xref ref-type="bibr" rid="B195">Yu et al., 2014</xref>). Based on its expression levels, GPER holds promise as both a prognostic indicator and therapeutic target. Upon binding with an agonist, GPER is activated, playing a crucial role in the initiation and progression of tumors. Its diverse functions include the regulation of cell proliferation, invasion, metastasis, angiogenesis, modulation of cancer-associated fibroblasts (CAF), control of tumor stem cell functionality, cytokine production and secretion, and evasion of immune responses (<xref ref-type="fig" rid="F1">Figures 1B,C</xref>). However, the function of GPER in TNBC and its potential effectiveness in combating highly invasive TNBC remain controversial. GPER overexpression is positively associated with metastatic capability, tumor size, HER2/neu and poor survival (<xref ref-type="bibr" rid="B157">Steiman et al., 2013</xref>). Using GPER-specific small interfering RNA (siRNA) knockdown, complete elimination of GPER expression was demonstrated, abolishing the stimulation of certain signaling pathways responsible for amplifying proliferation, and further substantiating the significant role of GPER in promoting the proliferation of breast cancer (<xref ref-type="bibr" rid="B61">Girgert et al., 2012</xref>). The potential involvement of GPER-associated signaling pathways in cell invasion and migration has also been demonstrated (<xref ref-type="bibr" rid="B195">Yu et al., 2014</xref>; <xref ref-type="bibr" rid="B141">Rigiracciolo et al., 2019</xref>; <xref ref-type="bibr" rid="B188">Ye et al., 2019</xref>; <xref ref-type="bibr" rid="B191">Yin et al., 2020</xref>). <italic>In vivo</italic> studies revealed that breast cancer in GPER-knockout mice resulted in diminished lung metastases compared with that in wild-type mice, indicating that animals with low or no GPER expression tend to develop less aggressive breast tumors (<xref ref-type="bibr" rid="B115">Marjon et al., 2014</xref>). Recent research has shown a significant correlation between GPER abundance and high-risk TNBC, characterized by G3 tumors, distant metastasis, stage III, and lymph node metastasis (<xref ref-type="bibr" rid="B185">Xu et al., 2022</xref>). Differing opinions suggest that GPER expression may suppress tumor initiation and progression (<xref ref-type="bibr" rid="B182">Wei&#xdf;enborn et al., 2014</xref>). GPER inhibits tumor cell growth by stimulating G2/M-phase cell cycle arrest, decreasing cyclin B expression, and promoting apoptosis in ER&#x03b1;-negative breast cancer cells (<xref ref-type="bibr" rid="B179">Wei et al., 2014</xref>). <xref ref-type="bibr" rid="B181">Weissenborn et al. (2017)</xref> suggested that TNBC with downregulated GPER expression has a poor outcome, which may be associated with promoter methylation changes in GPER. Additionally, TNBC models treated with GPER-specific agonists exhibited reduced distant migration ability and angiogenesis of tumor cells both <italic>in vivo</italic> and <italic>in vitro</italic>, leading to a significant reduction in lung metastasis (<xref ref-type="bibr" rid="B28">Chen et al., 2016</xref>).</p>
</sec>
</sec>
<sec id="s3">
<title>3 Mechanism of GPER in TNBC</title>
<p>ERs, such as ER&#x3b1;, belong to the nuclear receptor superfamily. E2 activates ER&#x3b1; in the cell nucleus, forming a dimer. The activated ER&#x3b1; causes gene expression in the nucleus by directly binding to estrogen response elements in the genome or by binding to other transcription factors and their response elements (<xref ref-type="bibr" rid="B83">Kato et al., 2005</xref>). This genomic effect is relatively slow but is an important pathway for estrogen to promote breast cancer growth (<xref ref-type="bibr" rid="B178">Watters et al., 1997</xref>). Additionally, a small fraction of ER&#x3b1; is localized to the cell membrane, enabling E2 to induce non-genomic effects through this membrane-bound ER&#x3b1;. Upon encountering E2 on the cell membrane, ER&#x3b1; rapidly activates the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway, which is a non-genomic effect that significantly contributes to promoting cell proliferation (<xref ref-type="bibr" rid="B22">Catalano et al., 2009</xref>; <xref ref-type="bibr" rid="B133">Puglisi et al., 2019</xref>). Furthermore, E2-ER&#x3b1; binding on the membrane activates the non-receptor tyrosine kinase SRC, which phosphorylates and activates aromatase, thereby promoting <italic>de novo</italic> synthesis of E2. This positive feedback effect also contributes to the genomic signaling of E2-ER&#x3b1;. Moreover, ER&#x3b1; signaling exhibits a ligand-independent activation pathway, exerting its effects through phosphorylation changes in ER&#x3b1; (<xref ref-type="bibr" rid="B180">Weigel and Zhang, 1998</xref>). Unlike the classic E2/ER&#x3b1; action pathway, E2-GPER primarily exerts its effects through fast, non-genomic signaling pathways. Distinguishing itself from ER&#x3b1;, which directly activates gene transcription by binding to transcriptional regulatory sites on DNA, GPER&#x2019;s transcriptional effects are mediated indirectly through cAMP and EGFR. In breast cancer cell lines, E2-activated GPER couples to a trimeric G protein, and the G&#x3b1; subunit dimer directly stimulates adenylyl cyclase, which in turn converts adenosine triphosphate into cAMP. In contrast, the G&#x3b2;&#x3b3; subunit dimer activates SRC tyrosine kinase, thereby activating &#x3b1;5&#x3b2;1 integrin and matrix metalloproteinase (MMP). Subsequently, the heparin-binding EGF-like growth factor is activated and stimulates EGFR transactivation (<xref ref-type="bibr" rid="B51">Filardo et al., 2000</xref>; <xref ref-type="bibr" rid="B54">Filardo and Thomas, 2005</xref>; <xref ref-type="bibr" rid="B165">Thomas et al., 2005</xref>; <xref ref-type="bibr" rid="B53">Filardo et al., 2008</xref>). This subsequently activates intracellular signaling events, specifically the PI3K/Akt and ERK1/2 pathways (<xref ref-type="bibr" rid="B132">Prossnitz et al., 2008</xref>). These two transcriptional pathways are regulated by cAMP-regulated enhancers and serum-regulated enhancers, respectively. After GPER transcriptional activation, genes for c-Fos, cyclins A, cyclins D1, and connective tissue growth factor (CTGF), which are involved in the biological processes of breast cancer, are upregulated. For example, CTGF is a cytokine that enhances the migration ability of the MDA-MB-231 cell line (<xref ref-type="bibr" rid="B134">Pupo et al., 2017</xref>). Moreover, in SKBR3 cells, which are ER&#x3b1;-negative, rapid transcriptional activation of c-Fos is induced by estradiol through activation of GPER/EGFR/mitogen-activated protein kinase (MAPK) signaling cascades (<xref ref-type="bibr" rid="B113">Maggiolini et al., 2004</xref>). The transcription factor c-Fos is an important invasion regulator in human mammary carcinomas, impacting cell migration, morphology, and proteolytic degradation of basal membranes (<xref ref-type="bibr" rid="B118">Milde-Langosch et al., 2004</xref>). The GPER mechanisms of action in TNBC and comprehensive molecular pathways are presented in <xref ref-type="fig" rid="F2">Figure 2</xref>.</p>
<fig id="F2" position="float">
<label>FIGURE 2</label>
<caption>
<p>Molecular pathways mediated by G protein-coupled estrogen receptor in triple-negative breast cancer. Abbreviations: NMDAR, N-methyl-d-aspartate receptor; CAMK, Ca2&#x2b;/calmodulin-dependent protein kinase; MEK, mitogen-activated protein kinase; MAPK, mitogen-activated protein kinase; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element-binding protein; CBP, CREB-binding protein; VGLUT2, vesicular glutamate transporter 2; HOTAIR, HOX transcript antisense intergenic RNA; HB-EGF, heparin-binding EGF-like growth factor; BCL-2, B-cell lymphoma 2; CTGF, connective tissue growth factor; EGR1: early growth response protein 1; HLA-G, human leukocyte antigen-G; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; SRC, steroid receptor coactivator.</p>
</caption>
<graphic xlink:href="fcell-12-1338448-g002.tif"/>
</fig>
<sec id="s3-1">
<title>3.1 GPER-activated cell signaling and the progression of TNBC</title>
<p>Elevated GPER expression is directly related to a poor prognosis in TNBC (<xref ref-type="bibr" rid="B157">Steiman et al., 2013</xref>; <xref ref-type="bibr" rid="B185">Xu et al., 2022</xref>). Specifically, decreasing GPER expression with siRNA has been demonstrated to effectively inhibit the proliferation of TNBC cells (<xref ref-type="bibr" rid="B61">Girgert et al., 2012</xref>; <xref ref-type="bibr" rid="B62">2014</xref>). In addition, G-1 has been shown to stimulate tissue proliferation by increasing mitosis (<xref ref-type="bibr" rid="B149">Scaling et al., 2014</xref>). Therefore, we summarized the relevant GPER mechanisms of action in TNBC cells.</p>
<sec id="s3-1-1">
<title>3.1.1 GPER/ERK non-genomic signaling</title>
<p>GPER plays a pivotal role in numerous types of cancer, including endometrial cancer, thyroid cancer, melanoma, ovarian cancer, and breast cancer, via non-genomic signaling events (<xref ref-type="bibr" rid="B139">Revankar et al., 2005</xref>; <xref ref-type="bibr" rid="B170">Vivacqua et al., 2006</xref>; <xref ref-type="bibr" rid="B1">Albanito et al., 2007</xref>). <xref ref-type="bibr" rid="B195">Yu et al. (2014)</xref> observed that GPER was not only highly expressed in TNBC but was also involved in the activation of estrogen-mediated non-genomic ERK signaling. Based on clinicopathological evidence, p-ERK1/2 was detected in more than three-quarters of the GPER-positive TNBC specimens. Furthermore, high levels of GPER and p-ERK1/2 have been found to be prevalent in patients with a positive lymph nodes, large tumor size, and particularly an advanced clinical stage (<xref ref-type="bibr" rid="B195">Yu et al., 2014</xref>).</p>
<p>E2 or G-1 can induce Akt or ERK activation through GPER/EGFR signaling (<xref ref-type="bibr" rid="B1">Albanito et al., 2007</xref>; <xref ref-type="bibr" rid="B56">Fujiwara et al., 2012</xref>). Interestingly, <xref ref-type="bibr" rid="B195">Yu et al. (2014)</xref> found that in TNBC cells, E2, tamoxifen, and G-1 induced the rapid activation of p-ERK1/2 but not p-Akt signaling. Activation of GPER/EGFR/ERK upregulated proliferation-related genes, including genes for c-Fos, cyclin A, and cyclin D1, in MDA-MB-468 cells, thereby promoting cell cycle progression and proliferation. Additionally, E2/GPER/ERK significantly protected MDA-MB-468 cells when exposed to a serum-free medium through the upregulation of B-cell lymphoma (Bcl)-2 expression. This indicates that GPER/ERK signaling contributes to cell growth and survival by increasing Bcl-2 levels in TNBC cells (<xref ref-type="bibr" rid="B195">Yu et al., 2014</xref>). The Na<sup>&#x2b;</sup>/H<sup>&#x2b;</sup> exchanger regulatory factor 1 (NHERF1) is a target actuator of estrogen signaling and is significantly downregulated in the early stages of TNBC. <xref ref-type="bibr" rid="B177">Wang et al. (2017)</xref> showed that NHERF1 co-localized with GPER in MDA-MB-231 cells, and overexpression of NHERF1 induced the inhibition of ERK1/2 and Akt signaling and proliferation of TNBC. Therefore, the activation of GPER/ERK non-genomic signaling is a crucial mechanism that triggers various downstream signaling pathways associated with cell proliferation in TNBC.</p>
</sec>
<sec id="s3-1-2">
<title>3.1.2 GPER/FAK transduction pathway</title>
<p>FAK is a cytoplasmatic protein tyrosine kinase and plays a crucial role in promoting tumor cell invasiveness, which is attributed to both kinase-independent and kinase-dependent scaffolding functions (<xref ref-type="bibr" rid="B77">Jean et al., 2014</xref>; <xref ref-type="bibr" rid="B161">Taliaferro-Smith et al., 2015</xref>; <xref ref-type="bibr" rid="B153">Shen et al., 2018</xref>; <xref ref-type="bibr" rid="B140">Rigiracciolo et al., 2021</xref>; <xref ref-type="bibr" rid="B199">Zhang et al., 2021</xref>). Notably, high expression of FAK has been observed in breast tumors. Increased levels of FAK in primary tumors are associated with a triple-negative phenotype, as well as invasive and metastatic breast cancer. Moreover, FAK amplification occurs during the early stages of breast tumorigenesis (<xref ref-type="bibr" rid="B93">Lark et al., 2005</xref>; <xref ref-type="bibr" rid="B110">Luo and Guan, 2010</xref>; <xref ref-type="bibr" rid="B65">Golubovskaya et al., 2014</xref>). Estrogen activates FAK via the GPER/c-SRC/mitogen-activated protein kinase kinase (MEK) transduction pathway, thereby mediating tumor cell proliferation and invasiveness (<xref ref-type="bibr" rid="B141">Rigiracciolo et al., 2019</xref>). <xref ref-type="bibr" rid="B141">Rigiracciolo et al. (2019)</xref> observed that GPER stimulated Y397 FAK phosphorylation and upregulated focal adhesions (FA) in invasive and metastatic TNBC. FAs are crucial subcellular structures that mediate cell adhesion to the extracellular matrix (ECM). Immunofluorescence studies have shown that GPER activation by E2 and G-1 leads to the involvement of FAK in signal transducer and activator of transcription (STAT)3 nuclear accumulation and changes in gene expression. As a critical factor in JAK/STAT signaling, STAT3 regulates tumor progression by controlling the cell cycle, apoptosis, angiogenesis, and immune evasion (<xref ref-type="bibr" rid="B74">Huang et al., 2010</xref>; <xref ref-type="bibr" rid="B75">Huynh et al., 2017</xref>). Additionally, both STAT3 and FAK participate in the regulation of GPER-mediated expression of multiple proliferation-associated genes, such as CTGF, c-Fos, and early growth response protein 1 (<xref ref-type="bibr" rid="B80">Joo et al., 2004</xref>; <xref ref-type="bibr" rid="B126">Pandey et al., 2009</xref>). Overall, estrogenic GPER signaling may promote the invasive ability of TNBC cells via FAK and STAT3.</p>
</sec>
<sec id="s3-1-3">
<title>3.1.3 Long non-coding RNA</title>
<p>Glutamate is a key compound in cell metabolism that stimulates certain downstream molecular mechanisms to promote the invasion and migration of cancer cells through the N-methyl-d-aspartate receptor (<xref ref-type="bibr" rid="B144">Rzeski et al., 2002</xref>; <xref ref-type="bibr" rid="B100">Li et al., 2018</xref>). Compared with HER2-positive and ER&#x3b1;-positive breast cancer cells, glutamate is heavily secreted in TNBC. Glutamate can induce the para secretion of hypoxia-inducible factor-1&#x3b1; (HIF-1&#x3b1;) in TNBC (<xref ref-type="bibr" rid="B13">Briggs et al., 2016</xref>). LncRNAs are the largest and most heterogeneous RNA family among the non-coding RNAs that participate in the normal biological behavior of cells. Dysregulation of lncRNA expression is conducive to the occurrence of malignant tumors. Notably, estrogen-induced lncRNAs are associated with the development of breast cancer (<xref ref-type="bibr" rid="B171">Volovat et al., 2020</xref>). Under the stimulation of G-1 or E2, GPER-regulated lncRNAs are downregulated, thereby increasing the transport activity of glutamate and the transcriptional activity of vesicular glutamate transporter 2 (VGLUT2). Upregulation of VGLUT2, in conjunction with GPER-cAMP/PKA signaling, leads to increased glutamate secretion through the lncRNA&#x2013;Glutamate&#x2013;VGLUT2 pathway. This facilitates the phosphorylation of N-methyl D-aspartate receptor subtype 2B and activates the glutamate N-methyl-D-aspartate receptor (<xref ref-type="bibr" rid="B196">Zeng et al., 2019</xref>). Furthermore, Ca<sup>2&#x2b;</sup>/calmodulin-dependent protein kinase and MEK/MAPK signaling are activated, thereby enhancing cAMP response element-binding protein (CREB) phosphorylation, resulting in the recruitment of CREB-binding protein to the promoter regions of MMP7, which participates in TNBC invasion (<xref ref-type="bibr" rid="B191">Yin J. et al., 2020</xref>).</p>
<p>Furthermore, HOX transcript antisense intergenic RNA (HOTAIR), a crucial lncRNA, can promote tumor cell progression and the survival of breast cancer stem cells (<xref ref-type="bibr" rid="B40">Deng et al., 2017</xref>) and serves as a predictor of adverse prognostic events in patients with breast cancer. E2-GPER increases HOTAIR levels in TNBC cells by suppressing microRNA-148a (miR-148a) expression. Several studies have documented a positive association between the expression of HOTAIR and the metastatic potential of TNBC (<xref ref-type="bibr" rid="B40">Deng et al., 2017</xref>; <xref ref-type="bibr" rid="B104">Lu et al., 2018</xref>; <xref ref-type="bibr" rid="B158">Sun et al., 2018</xref>). G-15 blocks the E2-induced upregulation of HOTAIR and reverses cell migration (<xref ref-type="bibr" rid="B162">Tao et al., 2015</xref>).</p>
</sec>
<sec id="s3-1-4">
<title>3.1.4 TNBC-related stem cells</title>
<p>Cancer stem cells are capable of self-renewal and differentiation, which enables them to initiate tumor growth in new areas and form new tumors (<xref ref-type="bibr" rid="B167">Valastyan and Weinberg, 2011</xref>). In the context of basal-like breast cancer, stem cells are often detected through the low expression of cluster of differentiation (CD) 24 and high expression of CD44 (<xref ref-type="bibr" rid="B73">Honeth et al., 2008</xref>; <xref ref-type="bibr" rid="B99">Li et al., 2013</xref>; <xref ref-type="bibr" rid="B122">O&#x2019;Conor et al., 2018</xref>). These cell subpopulations remain viable during chemotherapy or neoadjuvant endocrine therapy, implying their significance in the development of drug resistance (<xref ref-type="bibr" rid="B33">Creighton et al., 2009</xref>; <xref ref-type="bibr" rid="B34">Croker and Allan, 2012</xref>). Furthermore, TNBC have a higher abundance of therapy-resistant cancer stem cells than that of other subtypes, leading to increased mortality, treatment failure, and recurrence (<xref ref-type="bibr" rid="B73">Honeth et al., 2008</xref>; <xref ref-type="bibr" rid="B99">Li et al., 2013</xref>; <xref ref-type="bibr" rid="B112">Ma et al., 2014</xref>). <xref ref-type="bibr" rid="B203">Zhu et al. (2022)</xref> used a spheroid culture method to induce sphere formation in MDA-MB-468 cells and compared the malignant characteristics, GPER levels, and stemness-related markers between spherical and adherent cells. The results revealed increased expression of GPER and a high percentage of the CD44&#x2b;/CD24-subpopulation in spheroid MDA-MB-468 cells. Furthermore, enhanced tumor metastasis was observed. This indicated a close connection between GPER expression and the enhancement of stemness in malignant tumors. Additionally, both spheroid and adherent cells exhibited increased GPER expression after E2 treatment, whereas GPER expression decreased after G-15 treatment. These effects were most apparent in spheroid cells, indicating that GPER positively regulated the proliferation, invasiveness, and colony formation of TNBC cells in response to E2 signaling and that GPER expression is associated with the display of stemness characteristics (<xref ref-type="bibr" rid="B203">Zhu et al., 2022</xref>).</p>
</sec>
<sec id="s3-1-5">
<title>3.1.5 Ezrin proteins</title>
<p>Ezrin-radixin-moesin (ERM) proteins, which belong to the actin-binding family, play a vital role in bridging the gap between the plasma membrane and actin cytoskeleton (<xref ref-type="bibr" rid="B131">Ponuwei, 2016</xref>). ERM proteins have a significant impact on cancer cell polarity and migration by regulating cell signaling, cytoactivity, and the cytoskeleton (<xref ref-type="bibr" rid="B32">Clucas and Valderrama, 2014</xref>). Clinical and pathological evidence has revealed that GPER and ezrin protein expression have a positive relationship with TNBC pathological tissues. Additionally, the high co-expression of GPER/ezrin is strongly correlated with a poor patient prognosis, and a high GPER expression is linked to a poor prognosis in young patients with TNBC with elevated estrogen levels but not in patients post menopause. E2 has been reported to rapidly promote the phosphorylation of the ezrin protein through GPER or ER&#x3b2;, causing ezrin-dependent rearrangement of the cytoskeleton and F-actin remodeling, which stimulates the migration and invasion of ER&#x03b1;-negative cancer cells. Notably, the stimulation of GPER counteracts ezrin activation and migration induced by ER&#x3b2; in co-expressed GPER and ER&#x3b2; cells, such as MDA-MB-231 (<xref ref-type="bibr" rid="B202">Zhou et al., 2016</xref>). This could be attributed to the presence of a certain degree of mutual antagonism between ERs. Consequently, high GPER expression is a risk factor for TNBC in patients with high estrogen levels and is likely associated with the GPER-mediated activation of ezrin and its downstream pathways.</p>
</sec>
</sec>
<sec id="s3-2">
<title>3.2 GPER and breast cancer-associated fibroblasts</title>
<p>The malignant behavior of tumors is significantly correlated with the tumor microenvironment (TME) and CAFs, which are critical members of the TME and exhibit active migratory and invasive abilities in breast cancer (<xref ref-type="bibr" rid="B107">Luo et al., 2015</xref>; <xref ref-type="bibr" rid="B89">Lappano and Maggiolini, 2018</xref>). GPER is expressed in CAFs and acts as a transcriptional regulator of the CAF response to estrogen or G-1 (<xref ref-type="bibr" rid="B108">Luo et al., 2014</xref>). Additionally, GPER participates in the paracrine secretion of chemotactic, growth, and ECM-related factors by CAF, thereby triggering invasive behavior in breast tumor cells (<xref ref-type="bibr" rid="B135">Pupo et al., 2012</xref>), including F-actin reorganization, epithelial-mesenchymal transition (EMT), cancer cell migration, and angiogenesis (<xref ref-type="bibr" rid="B36">De Francesco et al., 2014</xref>). Moreover, activated GPER triggers a feed-forward loop, inducing the expression of interleukin (IL) 1&#x3b2;/IL1R1 target genes on CAF, thereby promoting the invasive characteristics of breast cancer cells (<xref ref-type="bibr" rid="B39">De Marco et al., 2016</xref>). Furthermore, both estrogen and G-1 can induce the upregulation of HIF-1&#x3b1; and vascular endothelial growth factor (VEGF) expression in CAFs, thereby promoting tumor angiogenesis (<xref ref-type="bibr" rid="B143">Roskoski, 2007</xref>; <xref ref-type="bibr" rid="B36">De Francesco et al., 2014</xref>). In TNBC, upregulated GPER in CAF may facilitate the expression of collagen type 1 and drive the crucial proliferation, invasion, and migration of cancer cells (<xref ref-type="bibr" rid="B187">Yang and Yao, 2019</xref>). The above evidence demonstrates that GPER exerts a pro-tumorigenic effect on tumor cell proliferation, invasion, and migration through CAF, regardless of hormone receptor status. These mechanisms are presented in <xref ref-type="fig" rid="F3">Figure 3</xref>.</p>
<fig id="F3" position="float">
<label>FIGURE 3</label>
<caption>
<p>The mechanism by which G protein-coupled estrogen receptor promotes triple-negative breast cancer progression through cancer-associated fibroblasts. Abbreviations: CAF, cancer-associated fibroblasts; VEGF, vascular endothelial growth factor; EMT, epithelial-mesenchymal transition; HIF-1&#x3b1;, hypoxia-inducible factor-1&#x3b1;; Coll-1, collagen type 1; IL1&#x3b2;, interleukin 1&#x3b2;; IL1R1, interleukin 1 receptor 1.</p>
</caption>
<graphic xlink:href="fcell-12-1338448-g003.tif"/>
</fig>
</sec>
<sec id="s3-3">
<title>3.3 Interaction of GPER with other hormone receptors in TNBC</title>
<p>The androgen receptor (AR) plays a vital role as a member of the nuclear receptor superfamily and participates in both physiological and pathological processes (<xref ref-type="bibr" rid="B116">Matsumoto et al., 2013</xref>; <xref ref-type="bibr" rid="B2">Anestis et al., 2020</xref>). Immunohistochemical staining of a TNBC tissue microarray containing 165 tumor specimens suggests that AR is positively correlated with tumor size, lymphatic metastasis, and high histological grade and negatively associated with GPER expression in TNBC (<xref ref-type="bibr" rid="B154">Shen et al., 2017</xref>). Dihydrotestosterone (DHT) enhances the proliferation of TNBC cells in a dose-dependent manner. Treatment with DHT leads to an upregulation of AR protein expression, whereas AR knockdown blocks the pro-proliferative effects induced by DHT. Intriguingly, DHT negatively regulates GPER expression, and AR deficiency significantly reduces the effectiveness of GPER suppression by DHT. Notably, the direct binding of AR to the GPER promoter, leading to negative regulation of GPER expression, is one of the contributing factors. The same conclusion was also observed <italic>in vivo</italic>, indicating that AR represses the pro-growth effects mediated by GPER in TNBC (<xref ref-type="bibr" rid="B154">Shen et al., 2017</xref>).</p>
<p>The prognostic influence of ER&#x3b2; in TNBC is also disputable, with some studies suggesting that ER&#x3b2; possesses anti-proliferative and -invasive functions in breast cancer cells, possibly by suppressing the PI3K/Akt/mTOR signaling pathway (<xref ref-type="bibr" rid="B97">Lei et al., 2020</xref>). In contrast, some studies have demonstrated that ER&#x3b2; mediates TNBC invasion by regulating EGFR (<xref ref-type="bibr" rid="B88">Kyriakopoulou et al., 2022</xref>). In a recent study, silencing GPER expression using siRNA resulted in a weakening in the invasiveness of TNBC cells expressing ER&#x3b2; while significantly enhancing the anti-invasive effects of ER&#x3b2; (<xref ref-type="bibr" rid="B150">Schmitz et al., 2022</xref>). Activated ER&#x3b2; suppresses tumor angiogenesis by downregulating VEGF protein levels (<xref ref-type="bibr" rid="B146">Salahuddin et al., 2022</xref>). However, GPER upregulates VEGF expression in breast cancer CAFs (<xref ref-type="bibr" rid="B39">De Marco et al., 2016</xref>). Additionally, in TNBC cells, the activation of GPER counteracts ezrin activation and migration induced by ER&#x3b2; (<xref ref-type="bibr" rid="B188">Ye et al., 2019</xref>). Despite the apparent opposition in the effects of ER&#x3b2; and GPER, their interaction mechanisms remain unclear and warrant further investigation.</p>
<p>As a classical ER&#x3b1; homologous orphan nuclear receptor, the overexpression of estrogen-related receptor &#x3b1; (ERR&#x3b1;) frequently correlates with unfavorable outcomes among individuals diagnosed with breast cancer (<xref ref-type="bibr" rid="B24">Cavallini et al., 2005</xref>; <xref ref-type="bibr" rid="B26">Chang et al., 2011</xref>). An <italic>in vitro</italic> study suggested that GPER-mediated estrogen-induced ERR&#x3b1; upregulation may promote TNBC cell viability, migration, and invasion. ERR&#x3b1;-GPER interactions lead to a malignant phenotype of TNBC, and this result was consistent with the conclusion drawn from the survival analysis (<xref ref-type="bibr" rid="B189">Ye et al., 2020</xref>). Additional research is necessary to determine the potential mechanisms that contribute to the interplay between GPER and ERR&#x3b1; in TNBC.</p>
</sec>
<sec id="s3-4">
<title>3.4 Effects of GPER on cytokines and chemokines</title>
<p>Activation of GPER has demonstrated effects on the synthesis of chemokines specific to white blood cells and intracellular signal transduction pathways, thereby governing the movement of immune cells and modulating inflammatory reactions. G-1 is an activator of GPER and promotes the synthesis of the anti-inflammatory cytokine IL-10 in CD4<sup>&#x2b;</sup> T lymphocytes (<xref ref-type="bibr" rid="B15">Brunsing and Prossnitz, 2011</xref>). G-1 suppresses the production of inflammatory molecules such as tumor necrosis factor (TNF), IL-6, and IL-12 in macrophages, which are triggered by lipopolysaccharides (<xref ref-type="bibr" rid="B9">Blasko et al., 2009</xref>). Following G-1-induced GPER activation, multiple genes, including GCSF, SOCS3, CXCL2, COX2, IL1RA, and IL1B, are upregulated through the p38 MAPK, ERK, and cAMP/PKA/CREB signaling pathways. Consequently, the production of CXCL8 protein is enhanced. Furthermore, GPER activation in neutrophils derived from healthy individuals enhanced the respiratory burst, cellular viability, and CD62L and CD11b activation marker levels (<xref ref-type="bibr" rid="B142">Rodenas et al., 2017</xref>).</p>
<p>Moreover, GPER interacts with specific chemokine receptors and cytokines, thereby impacting their signaling pathways and influencing physiological processes such as cell proliferation, migration, and tumor development. For example, the activation of GPER influences the synthesis of cytokines such as IL-6 and IL-8, which have important functions in promoting the growth and migration of cancer cells, particularly in low-oxygen environments (<xref ref-type="bibr" rid="B16">Bustos et al., 2017</xref>). In the case of breast cancer, the activation of GPER results in the suppression of nuclear factor kappa B (NF-&#x3ba;B) transcription, thereby decreasing the production of IL-6 induced by TNF&#x3b1; in the SKBR3 cell line. In addition, the activation of GPER is correlated with a reduction in IL-6 and VEGF-A levels in TNBC cellular models (<xref ref-type="bibr" rid="B123">Okamoto and Mizukami, 2016</xref>; <xref ref-type="bibr" rid="B102">Liang et al., 2017</xref>). Furthermore, GPER agonism by E2 inhibits TGF-&#x3b2; signaling in breast cancer (<xref ref-type="bibr" rid="B86">Kleuser et al., 2008</xref>). Both E2 and G-1 induce the release of IL-1&#x3b2; in CAFs, thereby resulting in an increase in the production of IL1R1. As a consequence of this molecular phenomenon, the invasive and migratory capabilities of breast cancer cells are heightened in the SKBR3 and MCF-7 cell lines. Notably, the absence of N-glycosylation in the N-terminal region of GPER causes the receptor to enter the nucleus, where it functions as a factor resembling transcription, thereby facilitating the upregulation of CTFG in CAFs and the SKBR3 cellular lineage (<xref ref-type="bibr" rid="B134">Pupo et al., 2017</xref>). Moreover, hypoxic conditions enhance the collaborative interaction between GPER and HIF1&#x3b1; in TNBC cells and CAF, thereby triggering the activation of the IL-&#x3b2;/IL1R1 signaling pathway and creating a feed-forward stimulatory loop. This causes changes in cytoskeleton structure and increased cellular activity, thus promoting TNBC invasiveness (<xref ref-type="bibr" rid="B92">Lappano et al., 2020</xref>).</p>
</sec>
<sec id="s3-5">
<title>3.5 GPER and immune evasion</title>
<p>GPER could mediate TNBC immune evasion and migration by regulating miR-148a in breast cancer. MiR-148a regulates tumor proliferation, invasion, and metastasis in various solid cancers by acting as an oncogene or cancer suppressor gene (<xref ref-type="bibr" rid="B105">Lujambio et al., 2008</xref>; <xref ref-type="bibr" rid="B145">Sakamoto et al., 2014</xref>). The miR-148a is specifically downregulated in TNBC (<xref ref-type="bibr" rid="B27">Chen et al., 2014</xref>). In their research, <xref ref-type="bibr" rid="B163">Tao et al. (2014)</xref> observed that estrogen-activated GPER inhibits miR-148a and stimulates the expression of human leukocyte antigen-G (HLA-G) in breast cancer (<xref ref-type="bibr" rid="B163">Tao et al., 2014</xref>). HLA-G is associated with the tumor-driven immune escape mechanism in the advanced stages of breast cancer (<xref ref-type="bibr" rid="B78">Jeong et al., 2014</xref>).</p>
<p>Furthermore, within the TME, the immune cells have significant contributions to tumor advancement. GPER expression is observed in diverse immune cells such as monocytes (<xref ref-type="bibr" rid="B87">Kvingedal and Smeland, 1997</xref>), natural killer cells (<xref ref-type="bibr" rid="B183">Wolfson et al., 2021</xref>), dendritic cells (<xref ref-type="bibr" rid="B142">Rodenas et al., 2017</xref>), macrophages (<xref ref-type="bibr" rid="B138">Rettew et al., 2010</xref>), polymorphonuclear cells (<xref ref-type="bibr" rid="B10">Blesson and Sahlin, 2012</xref>), as well as B and T lymphocytes. In breast cancer, the activation of GPER by various ligands elicits diverse responses within immune cells, influencing the constitution of the TME. Cytotoxic T lymphocytes (CTL) are the key effector cells in antitumor immunity and play an important role in immune responses against cancer. The activation of GPER leads to an elevation in IL-10 and IL-17, promoting the development of an immunosuppressive T cell phenotype. Furthermore, G-1 treatment leads to an upregulation of the programmed cell death 1 (PD-1) inhibitory receptor and CTL-associated protein 4 (CTLA-4) on isolated Foxp3&#x2b; regulatory T cells (Tregs) (<xref ref-type="bibr" rid="B172">Wang et al., 2009</xref>; <xref ref-type="bibr" rid="B14">Brunsing et al., 2013</xref>). The clinical significance of CTLA-4 and PD-1 expression in targeted cancer treatment has been acknowledged due to their ability to inhibit T cell proliferation (<xref ref-type="bibr" rid="B201">Zhao et al., 2018</xref>; <xref ref-type="bibr" rid="B151">Segovia-Mendoza et al., 2021</xref>). Thus, it is conceivable that GPER promotes the expression of PD-1 and CTLA-4 in Tregs derived from patients with breast cancer, thereby supporting the advancement of cancer. Furthermore, the use of GPER antagonists would favor the immune response against the tumor. In addition, GPER antagonists may also favor the clinical outcome of immunological checkpoints by reducing the expression of PD-1 and CTLA-4. The potential therapeutic approach of combining GPER antagonists with immunotherapy may serve as a strategy to boost the immune response and suppress the proliferation of breast cancer cells in patients.</p>
</sec>
</sec>
<sec id="s4">
<title>4 Bi-faceted role of GPER in TNBC</title>
<p>Several studies have reported the antitumor functions of GPER. Our recent meta-analysis suggested that high GPER mRNA expression indicates improved overall survival in patients with ER&#x03b1;-positive breast cancer. Furthermore, subgroup analysis indicated that this may be related to the cytoplasmic expression of GPER (<xref ref-type="bibr" rid="B197">Zhang et al., 2022</xref>). <xref ref-type="bibr" rid="B52">Filardo et al. (2002)</xref> observed that the transfection of MDA-MB-231 cells with GPER stimulates adenylyl cyclase and inhibits EGFR-induced ERK1/2 activity (<xref ref-type="bibr" rid="B52">Filardo et al., 2002</xref>). Therefore, in TNBC, estrogen stimulation by GPER activation may have two different effects on the ERK1/2 pathway.</p>
<p>NF-&#x3ba;B regulates the main EMT transcription factors, including SNAIL1, SLUG, TWIST1, and SIP1, which are associated with the progression in breast cancer (<xref ref-type="bibr" rid="B127">Park et al., 2007</xref>; <xref ref-type="bibr" rid="B129">Pires et al., 2017</xref>). In TNBC, NK-&#x3ba;B plays an important role in the GPER-mediated inhibition of malignant tumor biological behaviors (<xref ref-type="bibr" rid="B28">Chen et al., 2016</xref>). <xref ref-type="bibr" rid="B28">Chen et al. (2016)</xref> reported that the activation of GPER by G-1 downregulates NF-&#x3ba;B activities and cytoskeletal protein fibronectin expression, and inhibits EMT in TNBC, resulting in a reduction in the aggressive characteristics of breast cancer. Wang et al. reported that E2-and G-1-activated GPER inhibit the expression and nuclear localization of NF-&#x3ba;B and STAT3 and suppress tumor angiogenesis and proliferation in MDA-MB-468 xenografts (<xref ref-type="bibr" rid="B173">Wang C. et al., 2018</xref>). The IL-6 cytokine family is widely expressed across vertebrates as a signaling molecule and contributes significantly to the malignant phenotype of cancer (<xref ref-type="bibr" rid="B48">Felcher et al., 2022</xref>). IL-6-activated STAT3 (<xref ref-type="bibr" rid="B94">Lee et al., 2009</xref>; <xref ref-type="bibr" rid="B193">Yu et al., 2009</xref>) elevates HIF-1&#x3b1; levels in MDA-MB-231 cells, which induces VEGF-A and MMP transcription (<xref ref-type="bibr" rid="B184">Xu et al., 2005</xref>; <xref ref-type="bibr" rid="B46">Eichten et al., 2016</xref>; <xref ref-type="bibr" rid="B176">Wang K. et al., 2018</xref>). <xref ref-type="bibr" rid="B102">Liang et al. (2017)</xref> found that the expression of IL-6 and VEGF can be suppressed by GPER-inhibiting NF-&#x3ba;B promoter activity in TNBC cells. Furthermore, the forceful inhibition of IL-6 expression <italic>in vitro</italic> reduces colony formation and cell survival and suppresses tumor engraftment in TNBC cell lines (<xref ref-type="bibr" rid="B66">Hanahan and Weinberg, 2011</xref>; <xref ref-type="bibr" rid="B67">Hartman et al., 2013</xref>; <xref ref-type="bibr" rid="B48">Felcher et al., 2022</xref>). Hence, activated GPER inhibits the expression of NF-&#x3ba;B and its downstream signaling, which are crucial in the suppression of TNBC progression. Notably, focusing on the interaction between NF-&#x3ba;B and GPER for the exploration of future treatments for TNBC is crucial.</p>
<p>Opposing evidence regarding the effect of GPER on TNBC is notable and may be associated with several factors. First, the role of G-1, as a specific ligand for GPER, in cancer cell survival and proliferation remains debatable. Further, G-1 exhibits a high affinity for GPER at a concentration of 10&#xa0;nM and influences breast cancer cell proliferation in a dose-dependent manner (<xref ref-type="table" rid="T2">Table 2</xref>). Previous studies have suggested that G-1 promotes tumor cell proliferation within the range of 10&#xa0;nM&#x2013;1&#xa0;&#x3bc;M, whereas high concentrations inhibit proliferation. <xref ref-type="bibr" rid="B182">Wei&#xdf;enborn et al. (2014)</xref> found that GPER treated with 1&#xa0;&#x3bc;M G-1 inhibited TNBC cell growth. This inhibition was concentration-dependent and achieved by inducing cell cycle arrest in the G2/M phase, thereby enhancing the phosphorylation of histone h3, and promoting caspase-3-mediated apoptosis (<xref ref-type="bibr" rid="B182">Wei&#xdf;enborn et al., 2014</xref>). However, <xref ref-type="bibr" rid="B111">Lv et al. (2017)</xref> reported that the proliferation of TNBC cell lines was significantly inhibited by G-1 at relatively low concentrations (100&#xa0;nM). G-1 inhibits microtubule assembly by occupying colchicine-binding sites within breast cancer cells, thereby inducing cell cycle arrest and triggering apoptosis. Interestingly, this inhibitory effect was not affected by GPER knockdown. Therefore, G-1 may act as a microtubule-targeting agent to inhibit breast cancer cell proliferation (<xref ref-type="bibr" rid="B111">Lv et al., 2017</xref>). This conclusion is similar to that of <xref ref-type="bibr" rid="B174">Wang et al. (2011)</xref> who demonstrated that G-1 inhibits the growth of breast and ovarian cancer cells independent of GPER at the micromolar level. In the studies mentioned above, a concentration of 1&#xa0;&#xb5;M was often used to assess the inhibitory effects of G-1 on breast cancer malignancy (<xref ref-type="bibr" rid="B42">Dennis et al., 2009</xref>; <xref ref-type="bibr" rid="B28">Chen et al., 2016</xref>; <xref ref-type="bibr" rid="B102">Liang et al., 2017</xref>). Consequently, based on this evidence, it is crucial for studies on the action of G-1 on breast cancer cells to consider both its effects on GPER and related signaling pathways and its non-GPER-dependent tumor inhibitory effect.</p>
<table-wrap id="T2" position="float">
<label>TABLE 2</label>
<caption>
<p>Effects of different G-1 concentrations on breast cancer cell lines.</p>
</caption>
<table>
<thead valign="top">
<tr>
<th align="left">G-1 concentration</th>
<th align="left">Experimental cell lines</th>
<th align="left">Results</th>
<th align="left">References</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="left">100&#xa0;nM</td>
<td align="left">MCF-7, MDA-MB-468, MDA-MB-231, MDA-MB-436</td>
<td align="left">G-1 activates GPER/ERK signaling which promotes TNBC cell viability and motility</td>
<td align="left">
<xref ref-type="bibr" rid="B195">Yu et al. (2014)</xref>
</td>
</tr>
<tr>
<td align="left">1&#xa0;&#x3bc;M</td>
<td align="left">MDA-MB-231, BT-549, MDA-MB-468, HS578T</td>
<td align="left">G-1 inhibited angiogenesis and migration of TNBC cells</td>
<td align="left">
<xref ref-type="bibr" rid="B102">Liang et al. (2017)</xref>
</td>
</tr>
<tr>
<td align="left">1&#xa0;&#x3bc;M</td>
<td align="left">MDAMB-231, BT-549</td>
<td align="left">Treatment with G-1 for 24 or 48&#xa0;h inhibited invasion of TNBC cells</td>
<td align="left">
<xref ref-type="bibr" rid="B28">Chen et al. (2016)</xref>
</td>
</tr>
<tr>
<td align="left">10<sup>&#x2212;8</sup>&#x2013;10<sup>&#x2212;5</sup>&#xa0;M</td>
<td align="left">SKBR3, MDA-MB-231</td>
<td align="left">G-1 inhibited the proliferation of cells in a time-dependent and concentration-dependent manner</td>
<td align="left">
<xref ref-type="bibr" rid="B179">Wei et al. (2014)</xref>
</td>
</tr>
<tr>
<td align="left">1&#xa0;&#x3bc;M</td>
<td align="left">MDA-MB-231, MCF-7, MDA-MB-468, HEK-293</td>
<td align="left">G-1 inhibited the proliferation of breast cancer cells</td>
<td align="left">
<xref ref-type="bibr" rid="B182">Wei&#xdf;enborn et al. (2014)</xref>
</td>
</tr>
<tr>
<td align="left">500&#xa0;nM, 1&#xa0;&#x3bc;M, 2&#xa0;&#x3bc;M</td>
<td align="left">MDA-MB-231, HEK-293</td>
<td align="left">G-1 suppressed TNBC cell proliferation</td>
<td align="left">
<xref ref-type="bibr" rid="B174">Wang et al. (2011)</xref>
</td>
</tr>
<tr>
<td rowspan="2" align="left">1&#x2013;10&#xa0;nM, 100&#xa0;nM</td>
<td align="left">SKBR3, MCF-7</td>
<td align="left">G-1 had no obvious effect on cell proliferation</td>
<td rowspan="2" align="left">
<xref ref-type="bibr" rid="B111">Lv et al. (2017)</xref>
</td>
</tr>
<tr>
<td align="left">MDA-MB-231</td>
<td align="left">G-1 inhibited breast cancer cell line proliferation</td>
</tr>
<tr>
<td align="left">1&#xa0;&#x3bc;M</td>
<td align="left">Breast CAFs</td>
<td align="left">G-1 enhanced CAF proliferation after 72-h culture</td>
<td align="left">
<xref ref-type="bibr" rid="B108">Luo et al. (2014)</xref>
</td>
</tr>
<tr>
<td align="left">1&#xa0;&#x3bc;M</td>
<td align="left">Breast CAFs, SKBR3</td>
<td align="left">G-1 induced mRNA expression of VEGF.</td>
<td align="left">
<xref ref-type="bibr" rid="B36">De Francesco et al. (2014)</xref>
</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn>
<p>Abbreviations: TNBC, triple-negative breast cancer; ERK, extracellular signal-regulated kinase; CAF, cancer-associated fibroblast; VEGF, vascular endothelial growth factor.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<p>In addition, TNBC is an extremely heterogeneous cancer that can be classified into multiple subtypes, each with a distinct gene expression profile, resulting in significant differences in treatment response and prognosis. Moreover, differences in cell types, treatment conditions, and GPER subcellular localization may contribute to the previously discussed variations. Hence, further studies are required to fully elucidate the role of GPER in TNBC.</p>
</sec>
<sec id="s5">
<title>5 Prospects for GPER in TNBC therapy</title>
<sec id="s5-1">
<title>5.1 Agonists of GPER</title>
<p>Ligand-activated GPER can promote TNBC progression. GPER ligands mainly include endogenous estrogen, exogenous estrogen, estrogen analogs, and specific ligands. Reducing biologically available estrogen may be an effective strategy to block GPER effects. There are various methods to treat patients with ER&#x3b1;-positive breast cancer through blocking estrogen. These methods include ovarian removal, inhibiting ovarian function by activating gonadotrophin-releasing hormone, or using aromatase inhibitors to suppress estrogen synthesis. Investigating the specific subgroup of TNBC that could potentially benefit from estrogen deprivation strategies represents a promising avenue for future research.</p>
<p>With regards to the dual role of GPER in TNBC, certain GPER-specific agonists, such as G-1 could also inhibit the progression of TNBC. Berberine (BBR) is a bioactive isoquinoline alkaloid that acts as an agonist of GPER to inhibit the nuclear translocation of the NF-&#x3ba;B subunit RELA/p65. BBR also significantly inhibits TNBC by modulating GPER protein levels (<xref ref-type="bibr" rid="B136">Qi et al., 2021</xref>). The small-molecule targeted agonist of GPER, LNS8801, has demonstrated impressive results in a multicenter Phase 1&#x2013;2A clinical trial, exhibiting encouraging anti-tumor effects in patients with metastatic uveal melanoma, whether used alone or in combination with pembrolizumab. Additionally, LNS8801 alone or in combination with pembrolizumab was well tolerated and did not result in unexpected toxicity (<xref ref-type="bibr" rid="B155">Shoushtari et al., 2023</xref>). As shown in <xref ref-type="table" rid="T1">Table 1</xref>, a series of GPER agonists have been identified, showing different mechanisms of action. Notably, limited progress has been made in the development of effective GPER agonists for the treatment of breast cancer. Chrysin is a flavone that exhibits anti-cancer effects against various types of cancers (<xref ref-type="bibr" rid="B85">Kim et al., 2017</xref>) including TNBC (<xref ref-type="bibr" rid="B186">Yang et al., 2014</xref>). Chrysin nanoparticles (NP) are polymers with improved bioavailability and water solubility. In TNBC, chrysin NPs inhibit the expression of MMPs by activating GPER and suppressing factors such as NF-&#x3ba;B, phosphorylated-JNK, and PI3K. MMP regulation is crucial for tumor growth, proliferation, and angiogenesis. These studies elucidate the inhibitory effects of chrysin NPs on TNBC (<xref ref-type="bibr" rid="B84">Kim and Jung, 2020</xref>); hence, further clinical trials are warranted.</p>
</sec>
<sec id="s5-2">
<title>5.2 Antagonists of GPER</title>
<p>Small-molecule antagonists of GPER mainly include G-15 and G-36. <italic>In vitro</italic> and <italic>in vivo</italic> studies have demonstrated that both have high GPER affinity and can inhibit the activity of breast tumor cells. However, there is currently a lack of supporting clinical evidence (<xref ref-type="bibr" rid="B42">Dennis et al., 2009</xref>; <xref ref-type="bibr" rid="B43">Dennis et al., 2011</xref>). Recently, <xref ref-type="bibr" rid="B37">DeLeon et al. (2020)</xref> discovered a novel GPER antagonist, 2-cyclohexyl-4-isopropyl-N-(4-methoxybenzyl) aniline (CIMBA), which effectively reduced estrogen-induced cholesterol gallstone formation in female mice by inhibiting GPER signaling. CIMBA exhibits fewer off-target effects than G-15 and G-36 do when binding to the receptor, and is less likely than both to bind to ER&#x3b1; at high concentrations. This novel antagonist also presents potential for further research in the field of cancer (<xref ref-type="bibr" rid="B37">DeLeon et al., 2020</xref>). As shown in <xref ref-type="table" rid="T1">Table 1</xref>, several antagonists have been identified to inhibit GPER. However, additional experimental verification is crucial to determine their efficacy in TNBC.</p>
</sec>
<sec id="s5-3">
<title>5.3 Downregulation of GPER expression</title>
<p>GPER, like most GPCRs, relies on the action of heterotrimeric G proteins for its signaling mechanism (<xref ref-type="bibr" rid="B121">Nieto Gutierrez and McDonald, 2018</xref>). Directly targeting G proteins is an effective strategy (<xref ref-type="bibr" rid="B17">Campbell and Smrcka, 2018</xref>). G protein inhibitors can disrupt the conformational activation of the GPCR-G&#x3b1;&#x3b2;&#x3b3; pathway. For instance, the plant-derived depsipeptide FR900359 inhibits the constitutively active G protein &#x3b1; subunit G&#x3b1;q in uveal melanoma, thereby halting tumor cell proliferation and inducing apoptosis (<xref ref-type="bibr" rid="B124">Onken et al., 2020</xref>). Additionally, &#x3b2;-adrenergic receptor kinase 1, as a G&#x3b2;&#x3b3; subunit sequestering peptide, blocks the activation of ERK1/2 in breast cancer cells (<xref ref-type="bibr" rid="B51">Filardo et al., 2000</xref>); an effect that requires further validation in animal models. Furthermore, somavert is a competitive growth hormone receptor inhibitor and is primarily used to treat acromegaly. However, treatment with somavert suppresses the expression of GPER in TNBC cells, inhibits EGFR activation, and downregulates proliferation-associated genes, such as genes for c-Fos and cyclin D (<xref ref-type="bibr" rid="B64">Girgert et al., 2018</xref>). Furthermore, gene therapy techniques, such as RNA interference or clustered regularly interspaced short palindromic repeats (CRISP)-CRISPR-associated protein 9, could be used to modulate GPER expression <italic>in vivo</italic>. However, these methods are predominantly experimental and are not yet widely used in clinical practice.</p>
</sec>
<sec id="s5-4">
<title>5.4 Targeting the interactions between GPER and other membrane proteins</title>
<p>The GPER-dependent transactivation of EGFR, which plays a key role in initiating signaling pathways and influencing cellular activities, is crucial for the cellular signal transduction and function mediated by GPER (<xref ref-type="bibr" rid="B137">Quinn et al., 2009</xref>). Gefitinib is an inhibitor of the EGFR tyrosine kinase domain and effectively suppresses cancer cell proliferation by downregulating EGFR signaling, particularly within TNBC (<xref ref-type="bibr" rid="B71">Herbst et al., 2004</xref>; <xref ref-type="bibr" rid="B8">Bernsdorf et al., 2011</xref>). Although clinical trials using gefitinib as a monotherapy for breast cancer have exhibited unsatisfactory results, immunohistochemical analysis of post-treatment breast tumors has revealed complete inhibition of EGFR phosphorylation (<xref ref-type="bibr" rid="B7">Baselga et al., 2005</xref>). <xref ref-type="bibr" rid="B63">Girgert et al. (2017)</xref> demonstrated that gefitinib inhibits the development of TNBC cells by reducing GPER expression induced by E2. GPER antagonists efficiently impede the activation of both GPER and EGFR induced by EGF. The interplay between GPER and EGFR suggests that a therapeutic approach involving a combination of GPER and EGFR inhibitors holds promise for combating breast cancer. However, this potential requires comprehensive exploration through clinical trials.</p>
<p>Furthermore, the activation of the insulin-like growth factor (IGF)-1/IGF 1 receptor (IGF-1R) system induces stimulatory effects via GPER in highly malignant neoplasms such as mesothelioma and lung tumors (<xref ref-type="bibr" rid="B6">Avino et al., 2016</xref>). Moreover, <xref ref-type="bibr" rid="B38">De Marco et al. (2013)</xref> revealed a bidirectional interaction between the IGF system and GPER that promotes drug resistance and cancer progression. GPER is essential for the migratory effects induced by zinc via the IGF-1R pathway in ER&#x3b1;-negative breast cancer cells (<xref ref-type="bibr" rid="B130">Pisano et al., 2017</xref>). In addition, the fibroblast growth factor (FGF) and FGF receptor (FGFR) axis constitute a pivotal signal transduction pathway that mediates the intricate interaction between cancer cells and tumor stroma. The GPER-selective agonist G-1 induces the expression and release of FGF2 in CAFs through the activation of GPER. Subsequently, the secreted FGF2 activates the FGF2/FGFR1 paracrine signaling cascade, thereby promoting the invasion and migration of TNBC cells (<xref ref-type="bibr" rid="B148">Santolla et al., 2019</xref>). The interplay between GPER and these membrane growth factor receptors (GFRs) presents opportunities for the development of novel pharmacological approaches to target breast cancer progression. Therefore, combining GPER and GFR inhibitors emerges as a potential therapeutic strategy and warrants further study.</p>
</sec>
</sec>
<sec sec-type="conclusion" id="s6">
<title>6 Conclusion</title>
<p>As a novel estrogen receptor, the biological role of GPER in TNBC has not yet been sufficiently elucidated compared with that in other breast cancer subtypes. This review presents a comprehensive overview of GPER, encompassing its subcellular structure, functional role, and internal molecular mechanisms. The analysis includes diverse ligand effects and the interactions between GPER and closely associated factors in TNBC. However, the impact of GPER on the malignant behavior of TNBC appears contradictory. Despite the existing studies, the feasibility of using GPER as a therapeutic target is insufficient, and further research is warranted.</p>
</sec>
</body>
<back>
<sec id="s7">
<title>Author contributions</title>
<p>DZ: Conceptualization, Visualization, Writing&#x2013;original draft, Writing&#x2013;review and editing. HC: Visualization, Writing&#x2013;review and editing. JW: Writing&#x2013;review and editing. JJ: Writing&#x2013;review and editing. MI: Writing&#x2013;review and editing. ZZ: Writing&#x2013;review and editing. SY: Conceptualization, Funding acquisition, Supervision, Validation, Visualization, Writing&#x2013;review and editing.</p>
</sec>
<sec sec-type="funding-information" id="s8">
<title>Funding</title>
<p>The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was funded by the Liaoning Province Science and Technology Project (Applied Basic Research Program) (grant number 2022JH2/101500066); Shenyang Science and Technology Bureau Project (grant number 21-173-9-69); and 345 Talent Project of Shengjing Hospital of China Medical University (to SY).</p>
</sec>
<ack>
<p>
<xref ref-type="fig" rid="F1">Figure 1</xref> was created with <ext-link ext-link-type="uri" xlink:href="http://BioRender.com">BioRender.com</ext-link>.</p>
</ack>
<sec sec-type="COI-statement" id="s9">
<title>Conflict of interest</title>
<p>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.</p>
</sec>
<sec sec-type="disclaimer" id="s10">
<title>Publisher&#x2019;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
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