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Estrogen receptor β, a regulator of androgen receptor signaling in the mouse ventral prostate

Significance Prostate cancer is an androgen receptor (AR)-dependent disease. Goals in treatment of prostate cancer include keeping low Gleason grades low and preventing development of the lethal disease castration-resistant metastatic prostate cancer. The present study revealed that ERβ modulates AR signaling by repressing AR driver RORc and increasing AR corepressor DACH1/2. Loss of ERβ resulted in up-regulation of genes whose expression is associated with poor prognosis in prostate cancer accompanied by down-regulation of tumor-suppressive or tumor-preventive genes. Treatment of mice with an ERβ agonist resulted in the nuclear import of PTEN and repression of AR signaling. ERβ may be a promising target for treating early stage prostate cancer to prevent cancer progression. As estrogen receptor β−/− (ERβ−/−) mice age, the ventral prostate (VP) develops increased numbers of hyperplastic, fibroplastic lesions and inflammatory cells. To identify genes involved in these changes, we used RNA sequencing and immunohistochemistry to compare gene expression profiles in the VP of young (2-mo-old) and aging (18-mo-old) ERβ−/− mice and their WT littermates. We also treated young and old WT mice with an ERβ-selective agonist and evaluated protein expression. The most significant findings were that ERβ down-regulates androgen receptor (AR) signaling and up-regulates the tumor suppressor phosphatase and tensin homolog (PTEN). ERβ agonist increased expression of the AR corepressor dachshund family (DACH1/2), T-cadherin, stromal caveolin-1, and nuclear PTEN and decreased expression of RAR-related orphan receptor c, Bcl2, inducible nitric oxide synthase, and IL-6. In the ERβ−/− mouse VP, RNA sequencing revealed that the following genes were up-regulated more than fivefold: Bcl2, clusterin, the cytokines CXCL16 and -17, and a marker of basal/intermediate cells (prostate stem cell antigen) and cytokeratins 4, 5, and 17. The most down-regulated genes were the following: the antioxidant gene glutathione peroxidase 3; protease inhibitors WAP four-disulfide core domain 3 (WFDC3); the tumor-suppressive genes T-cadherin and caveolin-1; the regulator of transforming growth factor β signaling SMAD7; and the PTEN ubiquitin ligase NEDD4. The role of ERβ in opposing AR signaling, proliferation, and inflammation suggests that ERβ-selective agonists may be used to prevent progression of prostate cancer, prevent fibrosis and development of benign prostatic hyperplasia, and treat prostatitis.