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ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer
- Source :
- Nature Medicine. May 1, 2016, p488, 13 p.
- Publication Year :
- 2016
-
Abstract
- The androgen receptor (AR) is overexpressed and hyperactivated in human castration-resistant prostate cancer (CRPC). However, the determinants of AR overexpression in CRPC are poorly defined. Here we show that retinoic acid receptorrelated orphan receptor g (ROR-γ) is overexpressed and amplified in metastatic CRPC tumors, and that ROR-γ drives AR expression in the tumors. ROR-γ recruits nuclear receptor coactivator 1 and 3 (NCOA1 and NCOA3, also known as SRC-1 and SRC-3) to an AR-ROR response element (RORE) to stimulate AR gene transcription. ROR-γ antagonists suppress the expression of both AR and its variant AR-V7 in prostate cancer (PCa) cell lines and tumors. ROR-γ antagonists also markedly diminish genomewide AR binding, H3K27ac abundance and expression of the AR target gene network. Finally, ROR-γ antagonists suppressed tumor growth in multiple AR-expressing, but not AR-negative, xenograft PCa models, and they effectively sensitized CRPC tumors to enzalutamide, without overt toxicity, in mice. Taken together, these results establish ROR-γ as a key player in CRPC by acting upstream of AR and as a potential therapeutic target for advanced PCa.<br />Persistent or reactivated signaling by the androgen receptor (AR), a member of the nuclear receptor (NR) superfamily, drives the progression of prostate cancer to a deadly form of the disease, [...]
Details
- Language :
- English
- ISSN :
- 10788956
- Database :
- Gale General OneFile
- Journal :
- Nature Medicine
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.454485190
- Full Text :
- https://doi.org/10.1038/nm.4070