Opposing roles of ERα and ERβ in the genesis and progression of adenocarcinoma in the rat ventral prostate

BACKGROUND Prostate cancer is a common malignancy in men and although hormone ablation therapy is effective, men develop hormone resistance. There is need for therapies applicable earlier, such as treatment of prostatic intraepithelial neoplasia (PIN). Estrogens besides androgens play a role in prostate cancer pathogenesis via two receptors ERa and ER beta and both receptors are thought to play different, opposing, roles with ERa having proliferative properties and ER beta having anti-proliferative properties. To differentiate between the roles both receptors play in prostate cancer an ERa and an ER beta agonist, ERA-45 and ERB-26, have been tested in a rodent model for prostate carcinogenesis. METHODS The influence of ERa on prostate cancer progression was studied in intact male rats treated with testosterone in combination with the ERa agonist, ERA-45 for either a long-term (20-week) period or a shorter term (6-week) period. The ER beta agonist was tested in the shorter term model in intact male rats treated with testosterone in combination with the ERa agonist, ERA-45, followed by administration of the ER beta agonist, ERB-26, during the last 2 weeks. RESULTS Treatment of rats with testosterone in combination with ERA-45 induced mild PIN lesions at 6 weeks and severe precancerous PIN lesions at 20 weeks. The ER beta agonist prevented the onset of PIN lesions at 6 weeks. Moreover, prostate epithelial cell apoptosis was increased and proliferation was decreased. CONCLUSION These findings confirm the opposing roles ERa and ER beta play in prostate carcinogenesis and suggest a therapeutic opportunity of ER beta for treating precancerous PIN lesions. Prostate 72:10131022, 2012. (c) 2011 Wiley Periodicals, Inc.