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      G-Protein Coupled Estrogen Receptor in Breast Cancer

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          Abstract

          The G-protein coupled estrogen receptor (GPER), an alternate estrogen receptor (ER) with a structure distinct from the two canonical ERs, being ERα, and ERβ, is expressed in 50% to 60% of breast cancer tissues and has been presumed to be associated with the development of tamoxifen resistance in ERα positive breast cancer. On the other hand, triple-negative breast cancer (TNBC) constitutes 15% to 20% of breast cancers and frequently displays a more aggressive behavior. GPER is prevalent and involved in TNBC and can be a therapeutic target. However, contradictory results exist regarding the function of GPER in breast cancer, proliferative or pro-apoptotic. A better understanding of the GPER, its role in breast cancer, and the interactions with the ER and epidermal growth factor receptor will be beneficial for the disease management and prevention in the future.

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          Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF.

          A Frackelton, E J Filardo, J Quinn … (2000)
          Estrogen rapidly activates the mitogen-activated protein kinases, Erk-1 and Erk-2, via an as yet unknown mechanism. Here, evidence is provided that estrogen-induced Erk-1/-2 activation occurs independently of known estrogen receptors, but requires the expression of the G protein-coupled receptor homolog, GPR30. We show that 17beta-estradiol activates Erk-1/-2 not only in MCF-7 cells, which express both estrogen receptor alpha (ER alpha) and ER beta, but also in SKBR3 breast cancer cells, which fail to express either receptor. Immunoblot analysis using GPR30 peptide antibodies showed that this estrogen response was associated with the presence of GPR30 protein in these cells. MDA-MB-231 breast cancer cells (ER alpha-, ER beta+) are GPR30 deficient and insensitive to Erk-1/-2 activation by 17beta-estradiol. Transfection of MDA-MB-231 cells with a GPR30 complementary DNA resulted in overexpression of GPR30 protein and conversion to an estrogen-responsive phenotype. In addition, GPR30-dependent Erk-1/-2 activation was triggered by ER antagonists, including ICI 182,780, yet not by 17alpha-estradiol or progesterone. Consistent with acting through a G protein-coupled receptor, estradiol signaling to Erk-1/-2 occurred via a Gbetagamma-dependent, pertussis toxin-sensitive pathway that required Src-related tyrosine kinase activity and tyrosine phosphorylation of tyrosine 317 of the Shc adapter protein. Reinforcing this idea, estradiol signaling to Erk-1/-2 was dependent upon trans-activation of the epidermal growth factor (EGF) receptor via release of heparan-bound EGF (HB-EGF). Estradiol signaling to Erk-1/-2 could be blocked by: 1) inhibiting EGF-receptor tyrosine kinase activity, 2) neutralizing HB-EGF with antibodies, or 3) down-modulating HB-EGF from the cell surface with the diphtheria toxin mutant, CRM-197. Our data imply that ER-negative breast tumors that continue to express GPR30 may use estrogen to drive growth factor-dependent cellular responses.
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            In vivo Effects of a GPR30 Antagonist

            Megan K. Dennis, Ritwik Burai, Chinnasamy Ramesh … (2009)
            Estrogen is central to many physiological processes throughout the human body. We have previously shown that the G protein-coupled receptor GPR30/GPER, in addition to classical nuclear estrogen receptors (ERα/β), activates cellular signaling pathways in response to estrogen. In order to distinguish between the actions of classical estrogen receptors and GPR30, we have previously characterized a selective agonist of GPR30, G-1 (1). To complement the pharmacological properties of G-1, we sought to identify an antagonist of GPR30 that displays similar selectivity against the classical estrogen receptors. Here we describe the identification and characterization of a G-1 analog, G15 (2) that binds to GPR30 with high affinity and acts as an antagonist of estrogen signaling through GPR30. In vivo administration of G15 reveals that GPR30 contributes to both uterine and neurological responses initiated by estrogen. The identification of this antagonist will accelerate the evaluation of the roles of GPR30 in human physiology.
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              Identification of a gene (GPR30) with homology to the G-protein-coupled receptor superfamily associated with estrogen receptor expression in breast cancer.

              Kristoffer H Ring, U Francke, C Carmeci … (1997)
              Using the technique of differential cDNA library screening, a cDNA clone was isolated from an estrogen receptor (ER)-positive breast carcinoma cell line (MCF7) cDNA library based upon the overexpression of this gene compared to an ER-negative cell line (MDA-MB-231). Sequence analysis of this clone determined that it shared significant homology to G-protein-coupled receptors. This receptor, GPCR-Br, was abundantly expressed in the ER-positive breast carcinoma cell lines MCF7, T-47D, and MDA-MB-361. Expression was absent or minimal in the ER-negative breast carcinoma cell lines BT-20, MDA-MB-231, and HBL-100. GPCR-Br was ubiquitously expressed in human tissues examined but was most abundant in placenta. GPCR-Br expression was examined in 11 primary breast carcinomas. GPCR-Br was detected in all 4 ER-positive tumors and only 1 of 7 ER-negative tumors. Based upon PCR analysis in hybrid cell lines, the gene for GPCR-Br (HGMW-approved symbol GPR30) was mapped to chromosome 7p22. The pattern of expression of GPCR-Br indicates that this receptor may be involved in physiologic responses specific to hormonally responsive tissues. Copyright 1997 Academic Press.
              Article 0 comments Cited 134 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: MDPI
                ISSN (Electronic): 1422-0067
                Publication date (Electronic): 14 January 2019
                Publication date Collection: January 2019
                Volume: 20
                Issue: 2
                Electronic Location Identifier: 306
                Affiliations
                [1 ]Ph.D. Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan; lhhsu@ 123456kfsyscc.org (L.-H.H.); yflin@ 123456tmu.edu.tw (Y.-F.L.)
                [2 ]Division of Pulmonary and Critical Care Medicine, Sun Yat-Sen Cancer Center, Taipei 112, Taiwan
                [3 ]Department of Medicine, National Yang-Ming University Medical School, Taipei 112, Taiwan
                [4 ]Department of Medical Oncology, Sun Yat-Sen Cancer Center, Taipei 112, Taiwan; nmchu@ 123456kfsyscc.org
                [5 ]School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan
                Author notes
                [* ]Correspondence: kaosh@ 123456tmu.edu.tw ; Tel.: +886-2-2736-1661 (ext. 3317); Fax: +886-2-2732-4510
                Author information
                https://orcid.org/0000-0003-3165-9177
                https://orcid.org/0000-0003-4618-0898
                Article
                Publisher ID: ijms-20-00306
                DOI: 10.3390/ijms20020306
                PMC ID: 6359026
                PubMed ID: 30646517
                SO-VID: 66eaa345-955c-4342-ba8c-c2a290c9192a
                Copyright © © 2019 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 29 November 2018
                Date accepted : 12 January 2019
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular biology
                Keywords: breast cancer,epidermal growth factor receptor,estrogen,estrogen receptor,g-protein coupled estrogen receptor
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: breast cancer, epidermal growth factor receptor, estrogen, estrogen receptor, g-protein coupled estrogen receptor

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