Title |
Androgen receptor splice variants activating the full-length receptor in mediating resistance to androgen-directed therapy
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Published in |
Oncotarget, March 2014
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DOI | 10.18632/oncotarget.1802 |
Pubmed ID | |
Authors |
Bo Cao, Yanfeng Qi, Guanyi Zhang, Duo Xu, Yang Zhan, Xavier Alvarez, Zhiyong Guo, Xueqi Fu, Stephen R. Plymate, Oliver Sartor, Haitao Zhang, Yan Dong |
Abstract |
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 ARv567es, 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, ARv567es 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 "rheostat" 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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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France | 1 | 100% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 1 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Portugal | 1 | <1% |
Unknown | 101 | 99% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Ph. D. Student | 24 | 24% |
Researcher | 21 | 21% |
Student > Master | 10 | 10% |
Student > Bachelor | 9 | 9% |
Other | 6 | 6% |
Other | 16 | 16% |
Unknown | 16 | 16% |
Readers by discipline | Count | As % |
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Biochemistry, Genetics and Molecular Biology | 26 | 25% |
Agricultural and Biological Sciences | 21 | 21% |
Medicine and Dentistry | 19 | 19% |
Pharmacology, Toxicology and Pharmaceutical Science | 6 | 6% |
Chemistry | 3 | 3% |
Other | 8 | 8% |
Unknown | 19 | 19% |