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

Wan Fu Wu, Laure Maneix, Jose Insunza, Ivan Nalvarte, Per Antonson, Juha Kere, Nancy Yiu Lin Yu, Virpi Tohonen, Shintaro Katayama, Elisabet Einarsdottir, Kaarel Krjutskov, Yu Bing Dai, Bo Huang, Wen Su, Margaret Warner, Jan Åke Gustafsson

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

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 co-repressor 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 glutathi-one 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.

Original languageEnglish (US)
Pages (from-to)E3816-E3822
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number19
DOIs
StatePublished - May 9 2017

Keywords

  • Cancer prevention
  • Inflammation
  • Nuclear receptor
  • TGFβ

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Estrogen receptor β, a regulator of androgen receptor signaling in the mouse ventral prostate'. Together they form a unique fingerprint.

Cite this