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Ariazi EA , Brailoiu E , Yerrum S , Shupp HA , Slifker MJ , Cunliffe HE , Black MA , Donato AL , Arterburn JB , Oprea TI , Prossnitz ER , Dun NJ , Jordan VC
The G protein-coupled receptor GPR30 inhibits proliferation of estrogen receptor-positive breast cancer cells
Cancer Res. 2010 Feb 1;70(3) :1184-94
PMID: 20086172    PMCID: PMC2879282   
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The G protein-coupled receptor GPR30 binds 17beta-estradiol (E(2)) yet differs from classic estrogen receptors (ERalpha and ERbeta). GPR30 can mediate E(2)-induced nongenomic signaling, but its role in ERalpha-positive breast cancer remains unclear. Gene expression microarray data from five cohorts comprising 1,250 breast carcinomas showed an association between increased GPR30 expression and ERalpha-positive status. We therefore examined GPR30 in estrogenic activities in ER-positive MCF-7 breast cancer cells using G-1 and diethylstilbestrol (DES), ligands that selectively activate GPR30 and ER, respectively, and small interfering RNAs. In expression studies, E(2) and DES, but not G-1, transiently downregulated both ER and GPR30, indicating that this was ER mediated. In Ca(2+) mobilization studies, GPR30, but not ERalpha, mediated E(2)-induced Ca(2+) responses because E(2), 4-hydroxytamoxifen (activates GPR30), and G-1, but not DES, elicited cytosolic Ca(2+) increases not only in MCF-7 cells but also in ER-negative SKBr3 cells. Additionally, in MCF-7 cells, GPR30 depletion blocked E(2)-induced and G-1-induced Ca(2+) mobilization, but ERalpha depletion did not. Interestingly, GPR30-coupled Ca(2+) responses were sustained and inositol triphosphate receptor mediated in ER-positive MCF-7 cells but transitory and ryanodine receptor mediated in ER-negative SKBr3 cells. Proliferation studies involving GPR30 depletion indicated that the role of GPR30 was to promote SKBr3 cell growth but reduce MCF-7 cell growth. Supporting this, G-1 profoundly inhibited MCF-7 cell growth, potentially via p53 and p21 induction. Further, flow cytometry showed that G-1 blocked MCF-7 cell cycle progression at the G(1) phase. Thus, GPR30 antagonizes growth of ERalpha-positive breast cancer and may represent a new target to combat this disease.
Ariazi, Eric A Brailoiu, Eugen Yerrum, Smitha Shupp, Heather A Slifker, Michael J Cunliffe, Heather E Black, Michael A Donato, Anne L Arterburn, Jeffrey B Oprea, Tudor I Prossnitz, Eric R Dun, Nae J Jordan, V Craig CA116662/CA/NCI NIH HHS/United States CA118100/CA/NCI NIH HHS/United States CA127731/CA/NCI NIH HHS/United States HL090804/HL/NHLBI NIH HHS/United States HL090804-01A2S109/HL/NHLBI NIH HHS/United States HL51314/HL/NHLBI NIH HHS/United States NS18710/NS/NINDS NIH HHS/United States P30CA006927/CA/NCI NIH HHS/United States U54MH084690/MH/NIMH NIH HHS/United States Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. United States Cancer research Cancer Res. 2010 Feb 1;70(3):1184-94. Epub 2010 Jan 19.