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

Ulla Simanainen, Keely McNamara, Yan Ru Gao, Stephen McPherson, Reena Desai, Mark Jimenez, David J. Handelsman

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

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)α immunoreactivity compared with very low ERα expression in intact males. Similarly, strong basal and luminal ERα expression was detected in PEARKO prostate of intact males, suggesting that epithelial AR activity regulated epithelial ERα expression. ERβ was strongly expressed in intact, castrated, and PEARKO prostate. However, strong clusters of epithelial ERβ 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 ERα expression in the prostate epithelial cells is regulated by local, epithelia-specific, androgendependent mechanisms, and this imbalance in the AR- and ERmediated signaling sensitizes the mature prostate to exogenous estrogens.

Original languageEnglish
Pages (from-to)E727-E735
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume301
Issue number4
DOIs
Publication statusPublished - 2011 Oct

Keywords

  • Androgen receptor
  • Androgen receptor gene targeting
  • Cre-LoxP technology
  • Estrogen sensitivity
  • Mouse model
  • Prostate epithelia

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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