Molecular Origin, Expression Regulation, and Biological Function of Androgen Receptor Splicing Variant 7 in Prostate...

The problem of resistance to therapy in prostate cancer (PCa) is multifaceted. Key determinants of drug resistance include tumor burden and growth kinetics, tumor heterogeneity, physical barriers, immune system and microenvironment, undruggable cancer drivers, and consequences of therapeutic pressures. With regard to the fundamental importance of the androgen receptor (AR) in all stages of PCa from tumorigenesis to progression, AR is postulated to have a continued critical role in castration-resistant prostate cancer (CRPC). Suppression of AR signaling mediated by the full-length AR (AR-FL) is the therapeutic goal of all AR-directed therapies. However, AR-targeting agents ultimately lead to AR aberrations that promote PCa progression and drug resistance. Among these AR aberrations, androgen receptor variant 7 (AR-V7) is gaining attention as a potential predictive marker for as well as one of the resistance mechanisms to the most current anti-AR therapies in CRPC. Meanwhile, development of next-generation drugs that directly or indirectly target AR-V7 signaling is urgently needed. In the present review of the current literature, we have summarized the origin, alternative splicing, expression induction, protein conformation, interaction with coregulators, relationship with AR-FL, transcriptional activity, and biological function of AR-V7 in PCa development and therapeutic resistance. We hope this review will help further understand the molecular origin, expression regulation, and role of AR-V7 in the progression of PCa and provide insight into the design of novel selective inhibitors of AR-V7 in PCa treatment.