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

Abstract

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 ERα and ERβ and both receptors are thought to play different, opposing, roles with ERα having proliferative properties and ERβ having anti-proliferative properties. To differentiate between the roles both receptors play in prostate cancer an ERα and an ERβ agonist, ERA-45 and ERB-26, have been tested in a rodent model for prostate carcinogenesis. The influence of ERα on prostate cancer progression was studied in intact male rats treated with testosterone in combination with the ERα agonist, ERA-45 for either a long-term (20-week) period or a shorter term (6-week) period. The ERβ agonist was tested in the shorter term model in intact male rats treated with testosterone in combination with the ERα agonist, ERA-45, followed by administration of the ERβ agonist, ERB-26, during the last 2 weeks. 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 ERβ agonist prevented the onset of PIN lesions at 6 weeks. Moreover, prostate epithelial cell apoptosis was increased and proliferation was decreased. These findings confirm the opposing roles ERα and ERβ play in prostate carcinogenesis and suggest a therapeutic opportunity of ERβ for treating precancerous PIN lesions.