RT Journal Article
SR Electronic
T1 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
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.06.14.496079
DO 10.1101/2022.06.14.496079
A1 Uttariya Pal
A1 Mohan Manjegowda
A1 Neha Singh
A1 Snigdha Saikia
A1 Betty S. Philip
A1 Deep Jyoti Kalita
A1 Avdhesh Kumar Rai
A1 Anupam Sarma
A1 Vandana Raphael
A1 Deepak Modi
A1 Amal Chandra Kataki
A1 Anil Mukund Limaye
YR 2022
UL http://biorxiv.org/content/early/2022/06/17/2022.06.14.496079.abstract
AB Purpose The purpose of this study was to assess the relationship between GPER, a seven transmembrane G-protein coupled estrogen receptor, and ERα in breast tumors, and to make inroads into the mechanistic basis and clinical significance.Methods TCGA-BRCA data was mined to examine the relationship between GPER and ERα expression. GPER mRNA, and protein expression were analyzed in ERα-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 17β-estradiol (E2) administration in juvenile or adult mice. The effect of E2, or propylpyrazoletriol (PPT, an ERα agonist) stimulation on GPER expression was studied in MCF-7 and T47D cells, with or without tamoxifen or ERα knockdown. ERα-binding to the GPER locus was explored by analysing ChIP-seq data (ERP000380), in silico prediction of estrogen response elements, and chromatin immunoprecipitation assay.Results Clinical data revealed significant positive association between GPER and ERα expression in breast tumors. The median GPER expression in ERα-positive tumors was significantly higher than ERα-negative tumors. High GPER expression was significantly associated with longer overall survival of patients with ERα-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 ERα-knockdown blocked the induction of GPER. Estrogen-mediated induction was associated with increased ERα occupancy in the upstream region of GPER.Conclusion GPER expression is positively associated with ERα in breast tumors, and a transcriptional target of the estrogen-ERα signalling axis. More in-depth studies are required to establish the significance of GPER-ERα co-expression, and their interplay in breast tumor development, progression, and treatment.Competing Interest StatementThe authors have declared no competing interest.