Estrogen receptor β exerts tumor suppressive effects in prostate cancer through repression of androgen receptor activity

Abstract

Estrogen receptor {beta} (ER{beta}) was first identified in the rodent prostate and is abundantly expressed in human and rodent prostate epithelium, stroma, immune cells and endothelium of the blood vessels. In the prostates of mice with inactivated ER{beta}, mutant phenotypes include epithelial hyperplasia and increased expression of androgen receptor (AR)-regulated genes, most of which are also upregulated in prostate cancer (PCa). ER{beta} is expressed in both basal and luminal cells in the prostate while AR is expressed in luminal but not in the basal cell layer which harbors the prostate stem cells. To investigate the mechanisms of action of ER{beta} and its potential cross-talk with AR, we used RNA-seq to study the effects of estradiol or the synthetic ligand, LY3201, in AR-positive LNCaP PCa cells which had been engineered to express ER{beta}. Transcriptomic analysis indicated relatively few changes in gene expression with ER{beta} overexpression, but robust responses following ligand treatments. There is significant overlap of responsive genes between the two ligands, as well as ligand-specific alterations. Gene set analysis of down-regulated genes identified an enrichment of androgen-responsive genes, such as FKBP5, CAMKK2, and TBC1D4. Consistently, AR transcript, protein levels, and transcriptional activity were down-regulated following ER{beta} activation. In agreement with this, we find that the phosphorylation of the CAMKK2 target, AMPK, was repressed by ligand-activated ER{beta}. Down-regulation of TBC1D4, a major regulator of glucose uptake in prostate, indicates that ER{beta} is changing glucose metabolism in the prostate. These findings suggest that ER{beta}-mediated signaling pathways are involved in the negative regulation of AR expression and activity, thus supporting a tumor suppressive role for ER{beta} in PCa.