Anterior prostate epithelial AR inactivation modifies estrogen receptor expression and increases estrogen sensitivity

Simanainen U, McNamara K, Gao YR, McPherson S, Desai R, Jimenez M, Handelsman DJ. Anterior prostate epithelial AR inactivation modifies estrogen receptor expression and increases estrogen sensitivity. Am J Physiol Endocrinol Metab 301: E727-E735, 2011. First published July 12, 2011; doi:10.1152/ajpendo.00580.2010.-Androgens influence prostate growth and development, so androgen withdrawal can control progression of prostate diseases. Although estrogen treatment was originally used to induce androgen withdrawal, more recently direct estrogen effects on the prostate have been recognized, but the nature of androgen-estrogen interactions within the prostate remain poorly understood. To characterize androgen effects on estrogen sensitivity in the mouse prostate, we contrasted models of castration-induced androgen withdrawal in the prostate stromal and epithelial compartments with a prostate epithelial androgen receptor (AR) knockout (PEARKO) mouse model of selective epithelial AR inactivation. Castration markedly increased prostate epithelial estrogen receptor (ER)alpha immunoreactivity compared with very low ER alpha expression in intact males. Similarly, strong basal and luminal ER alpha expression was detected in PEARKO prostate of intact males, suggesting that epithelial AR activity regulated epithelial ER alpha expression. ER alpha was strongly expressed in intact, castrated, and PEARKO prostate. However, strong clusters of epithelial ER alpha positivity coincided with epithelial stratification in PEARKO prostate. In vivo estrogen sensitivity was increased in PEARKO males, with greater estradiol-induced prostate growth and epithelial proliferation leading to squamous metaplasia, featuring markedly increased epithelial proliferation, thickening, and keratinization compared with littermate controls. Our results suggest that ER alpha expression in the prostate epithelial cells is regulated by local, epithelia-specific, androgen-dependent mechanisms, and this imbalance in the AR- and ER-mediated signaling sensitizes the mature prostate to exogenous estrogens.