Journal
ONCOTARGET
Volume 5, Issue 6, Pages 1646-1656Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.1802
Keywords
androgen receptor; splice variant; prostate cancer; castration resistance; enzalutamide
Categories
Funding
- Louisiana Board-of-Regents Grant [LEQSF(2012-15)-RD-A-25]
- Louisiana Cancer Research Consortium Fund
- Veterans Affairs Research Service
- National Natural Science Foundation of China [81272851]
- [NCI K01CA114252]
- [ACS RSG-07-218-01-TBE]
- [DOD W81XWH-12-1-0112]
- [W81XWH-12-1-0275]
- [P01-CA163227-01A1]
- [DOD-W81XWH-13-2-0093]
- [2 P50 CA 097186-12]
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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.
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