ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer.
ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer.
复制标题
ROR-gamma 驱动雄激素受体表达并代表去势抵抗性前列腺癌的治疗靶点
作者：
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 retinoid acid receptor-related orphan receptor γ (ROR-γ) is overexpressed and amplified in metastatic CRPC tumors, and that ROR-γ drives AR expression in the tumors. ROR-γ recruits coactivators SRC-1 and -3 to an AR-RORE to stimulate AR gene transcription. ROR-γ antagonists suppress the expression of AR and its variant AR-V7 in prostate cancer (PCa) cell lines and tumors. ROR-γ antagonists also markedly diminish genome-wide AR binding, H3K27ac abundance and expression of the AR gene network. Lastly, ROR-γ antagonists suppressed tumor growth in multiple AR-expressing but not AR-negative xenograft PCa models, and effectively sensitized CRPC tumors to enzalutamide, without overt toxicity in mice. Together, these results establish ROR-γ as a key player in CRPC by acting upstream of AR and a potential therapeutic target for advanced PCa.
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影响因子：
15.9
作者：
Qin, Jun;Lee, Hui-Ju;Tsai, Ming-Jer
通讯作者：
Tsai, Ming-Jer
影响因子：
50.3
作者：
Sharma, Naomi L.;Massie, Charlie E.;Neal, David E.
通讯作者：
Neal, David E.
影响因子：
11.5
作者：
Mostaghel, Elahe A.;Plymate, Stephen R.;Montgomery, Bruce
通讯作者：
Montgomery, Bruce
DOI：
10.1056/nejmoa1315815
发表时间：
2014-09-11
期刊：
The New England journal of medicine
影响因子：
--
作者：
Antonarakis ES;Lu C;Wang H;Luber B;Nakazawa M;Roeser JC;Chen Y;Mohammad TA;Chen Y;Fedor HL;Lotan TL;Zheng Q;De Marzo AM;Isaacs JT;Isaacs WB;Nadal R;Paller CJ;Denmeade SR;Carducci MA;Eisenberger MA;Luo J
通讯作者：
Luo J
影响因子：
4
作者：
Kumar, Naresh;Kojetin, Douglas J.;Solt, Laura A.;Kumar, K. Ganesh;Nuhant, Philippe;Duckett, Derek R.;Cameron, Michael D.;Butler, Andrew A.;Roush, William R.;Griffin, Patrick R.;Burris, Thomas P.
通讯作者：
Burris, Thomas P.