TY - JOUR
T1 - Estrogen receptor β, a regulator of androgen receptor signaling in the mouse ventral prostate
AU - Wu, Wan Fu
AU - Maneix, Laure
AU - Insunza, Jose
AU - Nalvarte, Ivan
AU - Antonson, Per
AU - Kere, Juha
AU - Yu, Nancy Yiu Lin
AU - Tohonen, Virpi
AU - Katayama, Shintaro
AU - Einarsdottir, Elisabet
AU - Krjutskov, Kaarel
AU - Dai, Yu Bing
AU - Huang, Bo
AU - Su, Wen
AU - Warner, Margaret
AU - Gustafsson, Jan Åke
PY - 2017/5/9
Y1 - 2017/5/9
N2 - 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.
AB - 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.
KW - Cancer prevention
KW - Inflammation
KW - Nuclear receptor
KW - TGFβ
UR - http://www.scopus.com/inward/record.url?scp=85019106985&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85019106985&partnerID=8YFLogxK
U2 - 10.1073/pnas.1702211114
DO - 10.1073/pnas.1702211114
M3 - Article
C2 - 28439009
AN - SCOPUS:85019106985
SN - 0027-8424
VL - 114
SP - E3816-E3822
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 19
ER -