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

// Bo Cao 1,2,* , Yanfeng Qi 1,* , Guanyi Zhang 2,3 , Duo Xu 1,2 , Yang Zhan 1 , Xavier Alvarez 4 , Zhiyong Guo 5 , Xueqi Fu 2 , Stephen R. Plymate 6,7 , Oliver Sartor 8,9 , Haitao Zhang 2,3 , and Yan Dong 1,10 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 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 “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.