The G-protein-coupled estrogen receptor, a gene co-expressed with ERα in breast tumors, is regulated by estrogen-ERα signalling in ERα positive breast cancer cells.

PurposeThe purpose of this study was to assess the relationship between GPER, a seven transmembrane G-protein coupled estrogen receptor, and ER in breast tumors, and to make inroads into the mechanistic basis and clinical significance. MethodsTCGA-BRCA data was mined to examine the relationship between GPER and ER expression. GPER mRNA, and protein expression were analyzed in ER-positive or -negative breast tumors from two cohorts using immunohistochemistry, western blotting, or RT-qPCR. The Kaplan-Meier Plotter was employed for survival analysis. The influence of estrogen in vivo was studied by examining GPER expression levels in estrus or diestrus mouse mammary tissues, and the impact of 17{beta}-estradiol (E2) administration in juvenile or adult mice. The effect of E2, or propylpyrazoletriol (PPT, an ER agonist) stimulation on GPER expression was studied in MCF-7 and T47D cells, with or without tamoxifen or ER knockdown. ER-binding to the GPER locus was explored by analysing ChIP-seq data (ERP000380), in silico prediction of estrogen response elements, and chromatin immunoprecipitation assay. ResultsClinical data revealed significant positive association between GPER and ER expression in breast tumors. The median GPER expression in ER-positive tumors was significantly higher than ER-negative tumors. High GPER expression was significantly associated with longer overall survival of patients with ER-positive tumors. In vivo experiments showed a positive effect of E2 on GPER expression. E2 induced GPER expression in MCF-7 and T47D cells; an effect mimicked by PPT. Tamoxifen or ER-knockdown blocked the induction of GPER. Estrogen-mediated induction was associated with increased ER occupancy in the upstream region of GPER. ConclusionGPER expression is positively associated with ER in breast tumors, and a transcriptional target of the estrogen-ER signalling axis. More in-depth studies are required to establish the significance of GPER-ER co-expression, and their interplay in breast tumor development, progression, and treatment.