{"paper_id":"22c833b1-8e88-40ae-ac9e-e1b24127fd4f","body_text":"Abstract\nRapid estrogen effects are mediated by membrane receptors, and evidence suggests a role for both a membrane-associated form of estrogen receptor alpha (ESR1; ERα) and G-protein coupled receptor 30 (GPER; GPR30). Considering estrogen’s importance in endometrial physiology and endometriosis pathophysiology, we hypothesized that GPER could be involved in both cyclic changes in endometrial estrogen action and that aberrant expression might be seen in the eutopic endometrium of women with endometriosis. Using real-time reverse transcriptase–polymerase chain reaction (RT-PCR) and immunohistochemical analysis of normal endometrium, endometrial samples demonstrated cycle-regulated expression of GPER, with maximal expression in the proliferative phase. Eutopic and ectopic endometrium from women with endometriosis overexpressed GPER as compared to eutopic endometrium of normal participants. Ishikawa cells, an adenocarcinoma cell line, expressed GPER, with increased expression upon treatment with estrogen or an ESR1 agonist, but not with a GPER-specific agonist. Decreased expression was seen in Ishikawa cells stably transfected with progesterone receptor A. Together, these data suggest that normal endometrial GPER expression is cyclic and regulated by nuclear estrogen and progesterone receptors, while expression is dysregulated in endometriosis.\nSimilar content being viewed by others\nReferences\nJensen EV, Desombre ER, Hurst DJ, Kawashima T, Jungblut PW. Estrogen-receptor interactions in target tissues. Arch Anat Microsc Morphol Exp. 1967;56(3):547–569\nMosselman S, Polman J, Dijkema R. ER beta: identification and characterization of a novel human estrogen receptor. FEBS Lett. 1996;392(1):49–53\nJensen EV, Jacobson HI. Basic guides to the mechanism of estrgen action. Recent Prog Horm Res. 1962;18:387\nGorski J, Toft D, Shyamala G, Smith D, Notides A. Hormone receptors: studies on the interaction of estrogen with the uterus. Rec Prog Horm Res. 1968;29:45\nFalkenstein E, Tillmann HC, Christ M, Feuring M, Wehling M. Multiple actions of steroid hormones—a focus on rapid, nongenomic effects. Pharmacol Rev. 2000;52(4):513–556\nPedram A, Razandi M, Levin ER. Nature of functional estrogen receptors at the plasma membrane. Mol Endocrinol. 2006;20(9):1996–2009\nRevankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER. A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science. 2005;307(5715):1625–1630\nBologa CG, Revankar CM, Young SM, et al. Virtual and biomolecular screening converge on a selective agonist for GPR30. Nat Chem Biol. 2006;2(4):207–212\nDennis MK, Burai R, Ramesh C, et al. In vivo effects of a GPR30 antagonist. Nat Chem Biol. 2009;5(6):421–427\nHazell G, Yao S, Roper J, Prossnitz E, O’Carroll AM, Lolait S. Localisation of GPR30, a novel G protein-coupled oestrogen receptor, suggests multiple functions in rodent brain and periph eral tissues. J Endocrinol. 2009;202(2):223–236\nHaas E, Meyer MR, Schurr U, et al. Differential effects of 17betaestradiol on function and expression of estrogen receptor alpha, estrogen receptor beta, and GPR30 in arteries and veins of patients with atherosclerosis. Hypertension. 2007;49(6):1358–1363\nWang C, Prossnitz ER, Roy SK. Expression of G protein-coupled receptor 30 in the hamster ovary: differential regulation by gonadotropins and steroid hormones. Endocrinology. 2007;148(10):4853–4864\nCarmeci C, Thompson DA, Ring HZ, Francke U, Weigel R. Identification of a gene (GPR30) with homology to the G-protein-coupled receptor superfamily associated with estrogen receptor expression in breast cancer. Genomics. 1997;45(3):607–617\nSmith HO, Leslie KK, Singh M, et al. GPR30: a novel indicator of poor survival for endometrial carcinoma. Am J Obstet Gynecol. 2007;196(4):386 e1–e9; discussion e9–e11\nHe YY, Cai B, Yang YX, Liu XL, Wan XP. Estrogenic G proteincoupled receptor 30 signaling is involved in regulation of endometrial carcinoma by promoting proliferation, invasion potential, and interleukin-6 secretion via the MEK/ERK mitogen-activated protein kinase pathway. Cancer Sci. 2009;100(6):1051–1061\nHuang GS, Gunter MJ, Arend RC, et al. Co-expression of GPR30 and ERbeta and their association with disease progression in uterine carcinosarcoma. Am J Obstet Gynecol. 2010;203(3):242. e1–e5\nVivacqua A, Bonofiglio D, Recchia AG, et al. The G proteincoupled receptor GPR30 mediates the proliferative effects induced by 17beta-estradiol and hydroxytamoxifen in endometrial cancer cells. Mol Endocrinol. 2006;20(3):631–646\nFilardo EJ, Quinn JA, Sabo E. Association of the membrane estrogen receptor, GPR30, with breast tumor metastasis and transactivation of the epidermal growth factor receptor. Steroids. 2008;73(9–10):870–873\nFilardo EJ, Quinn JA, Bland KI, Frackelton AR Jr. Estrogeninduced activation of Erk-1 and Erk-2 requires the G proteincoupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HBEGF. Mol Endocrinol. 2000;14(10):1649–1660\nLin BC, Suzawa M, Blind RD, et al. Stimulating the GPR30 estrogen receptor with a novel tamoxifen analogue activates SF-1 and promotes endometrial cell proliferation. Cancer Res. 2009;69(13):5415–5423\nWang A, Ji L, Shang W, et al. Expression of GPR30, ERalpha and ERbeta in endometrium during window of implantation in patients with polycystic ovary syndrome: a pilot study. Gynecol Endocrinol. 2011;27(4):251–255\nBulun SE. Endometriosis. N Engl J Med. 2009;360(3):268–279\nNoyes R, Hertig A, Rock J. Dating the endometrial biopsy. Fertil Steril. 1950;1:3–25\nIrwin JC, de las Fuentes L, Giudice LC. Growth factors and decidualization in vitro. Ann N Y Acad Sci. 1994 Sep 30; 734:7–18.\nRyan IP, Schriock ED, Taylor RN. Isolation, characterization, and comparison of human endometrial and endometriosis cells in vitro. J Clin Endocrinol Metab. 1994;78(3):642–649\nLi Q, Kannan A, Wang W, et al. Bone morphogenetic protein 2 functions via a conserved signaling pathway involving Wnt4 to regulate uterine decidualization in the mouse and the human. J Biol Chem. 2007;282(43):31725–31732\nRamathal CY, Bagchi IC, Taylor RN, Bagchi MK. Endometrial decidualization: of mice and men. Semin Reprod Med. 2010;28(1):17–26\nStauffer SR, Coletta CJ, Tedesco R, et al. Pyrazole ligands: structure-affinity/activity relationships and estrogen receptor-alpha-selective agonists. J Med Chem. 2000;43(26):4934–4947\nMeyers MJ, Sun J, Carlson KE, Marriner GA, Katzenellenbogen BS, Katzenellenbogen JA. Estrogen receptor-beta potency-selective ligands: structure-activity relationship studies of diarylpropionitriles and their acetylene and polar analogues. J Med Chem. 2001;44(24):4230–4251\nSmid-Koopman E, Blok LJ, Kuhne LC, et al. Distinct functional differences of human progesterone receptors A and B on gene expression and growth regulation in two endometrial carcinoma cell lines. J Soc Gynecol Investig. 2003;10(1):49–57\nBudwit-Novotny DA, McCarty KS, Cox EB, et al. Immuno-histochemical analyses of estrogen receptor in endometrial adenocarcinoma using a monoclonal antibody. Cancer Res. 1986;46(10):5419–5425\nHarrington WR, Sheng S, Barnett DH, Petz LN, Katzenellenbogen JA, Katzenellenbogen BS. Activities of estrogen receptor alpha-and beta-selective ligands at diverse estrogen responsive gene sites mediating transactivation or transrepression. Mol Cell Endocrinol. 2003;206(1–2):13–22\nPractice Committee of the American Society for Reproductive Medicine. Endometriosis and infertility. Fertil Steril. 2006;86(5 suppl 1):S156–S160\nBulun SE, Cheng YH, Pavone ME, et al. Estrogen receptor-beta, estrogen receptor-alpha, and progesterone resistance in endometriosis. Semin Reprod Med. 2010;28(1):36–43\nBulun SE, Cheng YH, Yin P, et al. Progesterone resistance in endometriosis: link to failure to metabolize estradiol. Mol Cell Endocrinol. 2006;248(1–2):94–103\nBurney RO, Talbi S, Hamilton AE, et al. Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis. Endocrinology. 2007;148(8):3814–3826\nFazleabas AT. Progesterone resistance in a baboon model of endometriosis. Semin Reprod Med. 2010;28(1):75–80\nKolkova Z, Noskova V, Ehinger A, Hansson S, Casslen BG. protein-coupled estrogen receptor 1 (GPER, GPR 30) in normal human endometrium and early pregnancy decidua. Mol Hum Reprod. 2010;16(10):743–751\nSanden C, Broselid S, Cornmark L, et al. G protein-coupled estrogen receptor 1/G protein-coupled receptor 30 localizes in the plasma membrane and traffics intracellularly on cytokeratin intermediate filaments. Mol Pharmacol. 2011;79(3):400–410\nLecce G, Meduri G, Ancelin M, Bergeron C, Perrot-Applanat M. Presence of estrogen receptor beta in the human endometrium through the cycle: expression in glandular, stromal, and vascular cells. J Clin Endocrinol Metab. 2001;86(3):1379–1386\nMatsuzaki S, Fukaya T, Suzuki T, Murakami T, Sasano H, Yajima A. Oestrogen receptor alpha and beta mRNA expression in human endometrium throughout the menstrual cycle. Mol Hum Reprod. 1999;5(6):559–564\nPress MF, Nousek-Goebl N, King WJ, Herbst AL, Greene GL. Immunohistochemical assessment of estrogen receptor distribution in the human endometrium throughout the menstrual cycle. Lab Invest. 1984;51(5):495–503\nMangal RK, Wiehle RD, Poindexter AN 3rd, Weigel NL. Differential expression of uterine progesterone receptor forms A and B during the menstrual cycle. J Steroid Biochem Mol Biol. 1997;63(4–6):195–202\nOtto C, Fuchs I, Kauselmann G, et al. GPR30 does not mediate estrogenic responses in reproductive organs in mice. Biol Reprod. 2009;80(1):34–41\nPandey DP, Lappano R, Albanito L, Madeo A, Maggiolini M, Picard D. Estrogenic GPR30 signalling induces proliferation and migration of breast cancer cells through CTGF. EMBO J. 2009;28(5):523–532\nZhang Z, Duan L, Du X, et al. The proliferative effect of estradiol on human prostate stromal cells is mediated through activation of ERK. Prostate. 2008;68(5):508–516\nAlbanito L, Madeo A, Lappano R, et al. G protein-coupled receptor 30 (GPR30) mediates gene expression changes and growth response to 17beta-estradiol and selective GPR30 ligand G-1 in ovarian cancer cells. Cancer Res. 2007;67(4):1859–1866\nVivacqua A, Bonofiglio D, Albanito L, et al. 17beta-estradiol, genistein, and 4-hydroxytamoxifen induce the proliferation of thyroid cancer cells through the g protein-coupled receptor GPR30. Mol Pharmacol. 2006;70(4):1414–1423\nAuthor information\nAuthors and Affiliations\nCorresponding author\nRights and permissions\nAbout this article\nCite this article\nPlante, B.J., Lessey, B.A., Taylor, R.N. et al. G Protein-Coupled Estrogen Receptor (GPER) Expression in Normal and Abnormal Endometrium. Reprod. Sci. 19, 684–693 (2012). https://doi.org/10.1177/1933719111431000\nPublished:\nIssue date:\nDOI: https://doi.org/10.1177/1933719111431000","source_license":"CC0","license_restricted":false}