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Proc Natl Acad Sci U S A. 2017 May 9;114(19):E3816-E3822. doi: 10.1073/pnas.1702211114. Epub 2017 Apr 24.

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

Author information

1
Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204.
2
Center for Innovative Medicine, Department of Biosciences and Nutrition, Karolinska Institutet, Novum, 14186 Stockholm, Sweden.
3
AstraZeneca-Shenzhen University Joint Institute of Nephrology, Centre for Nephrology & Urology, Shenzhen University Health Science Center, Shenzhen 518060, China.
4
Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204; jgustafsson@uh.edu.

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 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.

KEYWORDS:

TGFβ; cancer prevention; inflammation; nuclear receptor

PMID:
28439009
PMCID:
PMC5441728
DOI:
10.1073/pnas.1702211114
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

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