Abstract P105: GPER1 (G-protein Coupled Estrogen Receptor 1): A Molecular Target for Prostate Cancer Chemoprevention

Abstract

Incidence of Prostate Cancer (PCa), the 2nd most common cancer in men, is projected to increase by two-fold in 2040 and will pose as a potential healthcare burden. PCa pathogenesis involves a long latency period offering opportunities for chemoprevention. GPER1, a membrane-bound estrogen receptor has cell-context dependent functions. Activation of GPER1 with G1 (agonist) inhibited proliferation in vitro and in vivo. Thus, GPER1 may have tumour suppressive potential in PCa. However, GPER1’s potential as a chemopreventive target is unexplored. This prompted us to undertake the present study with a major goal to explore if GPER1 can be targeted for PCa chemoprevention. In-silico analysis of public datasets demonstrated a loss of GPER1 expression in high-grade human PCa compared to normal/Benign Prostatic Hyperplasia (BPH) tissues. Our studies demonstrated significantly reduced frequency of GPER1-positive cells in high-grade human PCa compared to BPH tissues. In the TRAMP mice, GPER1 expression and GPER1-positive cell frequency were significantly higher at the HGPIN (High-Grade Intraepithelial Neoplasia) stage and decreased at the Well-Differentiated Carcinoma (WDC) stage, compared to respective age-matched control animals. Further, promoter methylation analysis revealed an increase in the percent methylation at the 5CpG sites spanning the GPER1 promoter in TRAMP mice displaying HGPIN followed by a decrease in the animals displaying WDC, compared to respective age-matched control mice. In vivo pharmacological activation of GPER1 with G1 alone, not when co-administered with G15 (antagonist), inhibited progression of HGPIN to PCa in TRAMP mice. In vitro GPER1-silencing in prostate cell lines led to an increase in epithelial to mesenchymal transition (EMT) while G1-treatment led to a decrease in the proliferation and invasion in vitro. GPER1 mediated EMT was regulated through miR200a-ZEB2-E-Cadherin loop and other metastasis-associated genes. These observations highlight GPER1’s potential as a promising chemopreventive target and warrants studies to test GPER1 agonists for PCa chemoprevention in humans.