Oncotarget

Research Papers:

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

Bo Cao, Yanfeng Qi, Guanyi Zhang, Duo Xu, Yang Zhan, Xavier Alvarez, Zhiyong Guo, Xueqi Fu, Stephen R. Plymate, Oliver Sartor, Haitao Zhang and Yan Dong _

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Oncotarget. 2014; 5:1646-1656. https://doi.org/10.18632/oncotarget.1802

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Abstract

Bo Cao1,2,*, Yanfeng Qi1,*, Guanyi Zhang2,3, Duo Xu1,2, Yang Zhan1, Xavier Alvarez4, Zhiyong Guo5, Xueqi Fu2, Stephen R. Plymate6,7, Oliver Sartor8,9, Haitao Zhang2,3, and Yan Dong1,10

1 Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA

2 College of Life Sciences, Jilin University, China

3 Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA

4 Tulane National Primate Research Center, Covington, LA

5 Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD

6 Departments of Medicine, University of Washington School of Medicine, Seattle, WA

7 Department of Urology, University of Washington School of Medicine, Seattle, WA

8 Department of Urology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA

9 Department of Medicine, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA

10 National Engineering Laboratory for AIDS Vaccine, College of Life Sciences, Jilin University, China

* These authors contributed equally; in alphabetical order

Correspondence:

Yan Dong, Haitao Zhang, email:

Keywords: androgen receptor, splice variant, prostate cancer, castration resistance, enzalutamide

Received: February 18, 2014 Accepted: March 2, 2014 Published: March 4, 2014

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.  


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