Androgen receptor splice variants activating the full-length receptor in mediating resistance to androgen-directed therapy

作者：Cao Bo; Qi Yanfeng; Zhang Guanyi; Xu Duo; Zhan Yang; Alvarez Xavier; Guo Zhiyong; Fu Xueqi; Plymate Stephen R; Sartor Oliver; Zhang Haitao; Dong Yan^*

来源：Oncotarget, 2014, 5(6): 1646-1656.

DOI：10.18632/oncotarget.1802

• androgen receptor
• splice variant
• prostate cancer
• castration resistance
• enzalutamide

Upregulation of constitutively-active androgen receptor splice variants (AR-Vs) has been implicated in AR-driven tumor progression in castration-resistant prostate cancer. To date, functional studies of AR-Vs have been focused mainly on their ability to regulate gene expression independent of the full-length AR (AR-FL). Here, we showed that AR-V7 and AR(v567es), two major AR-Vs, both facilitated AR-FL nuclear localization in the absence of androgen and mitigated the ability of the antiandrogen enzalutamide to inhibit AR-FL nuclear trafficking. AR-V bound to the promoter of its specific target without AR-FL, but co-occupied the promoter of canonical AR target with AR-FL in a mutually-dependent manner. AR-V expression attenuated both androgen and enzalutamide modulation of AR-FL activity/cell growth, and mitigated the in vivo antitumor efficacy of enzalutamide. Furthermore, AR(v567es) levels were upregulated in xenograft tumors that had acquired enzalutamide resistance. Collectively, this study highlights a dual function of AR-Vs in mediating castration resistance. In addition to trans-activating target genes independent of AR-FL, AR-Vs can serve as a %26quot;rheostat%26quot; to control the degree of response of AR-FL to androgen-directed therapy via activating AR-FL in an androgen-independent manner. The findings shed new insights into the mechanisms of AR-V-mediated castration resistance and have significant therapeutic implications.

• 出版日期2014-3
• 单位吉林大学