Session: S74-Bench to Bedside: Cellular Signaling and Regulation of Steroid Receptor Function
Room 303 (Moscone Center)
Reactivation of androgen receptor (AR) transcriptional activity drives growth of castration-resistant prostate cancer (CRPC) through mechanisms including: upregulation of AR coactivators, expression of constitutively active AR splice variants, ligand-independent activation of AR and intracrine synthesis of androgens. Vav3, a growth factor-activated Rho GTPase guanine nucleotide exchange factor (GEF), is increased in numerous preclinical models of CRPC and in advanced/metastatic human disease. Further, Vav3 confers castration-resistant growth in vivo. Vav3 enhances AR activity by exploiting all mechanisms of AR reactivation in CRPC. Vav3 increases AR activity by both Vav3 GEF-dependent (requiring the Rho GTPase, Rac1) and GEF-independent mechanisms. We recently identified a novel nuclear action of Vav3 in AR coactivation and found that Vav3 strongly enhances the transcriptional activity of AR splice variants, including the prevalent AR3/AR-V7, thereby controling CRPC cell proliferation and survival. Vav3 and associated signaling components may serve as novel and valuable drug targets.
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