AR Alternative Splicing and Prostate Cancer Progression
Final rept. 1 Jul 2010-30 Jun 2013
MINNESOTA UNIV MINNEAPOLIS
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Androgen depletion therapy for advanced prostate cancer PCa invariably fails, and PCa recurs with an aggressive and lethal castration-resistant CR phenotype. Although androgen depletion inhibits activity of the androgen receptor AR, continued AR function is important for resistance to androgen depletion. Therefore, even though this stage of the disease is often referred to as androgen-independent AI, CRPCa remains an AR-dependent disease. Recently, alternatively-spliced, COOH-terminally truncated AR isoform variants have been identified in CRPCa cells and clinical tissues. These isoform variants function as constitutively active AR transcription factors that can support the CRPCa phenotype in model systems. The purpose of this project is to understand the mechanisms underlying increased expression and activity of these truncated AR isoform variants in CRPCa. Our work provides the first evidence that structural alterations in the AR gene may underlie disrupted AR splicing patterns at this stage of the disease. This knowledge could lead to better treatments or management of patients with CRPCa.
- Medicine and Medical Research