Role of androgen receptor splice variants in prostate cancer metastasis

Abstract

Prostate cancer (PCa) is one of the most lethal cancers in western countries. Androgen receptor (AR) signaling pathway plays a key role in PCa progression. Despite the initial effectiveness of androgen deprivation therapy (ADT) for treatment of patients with advanced PCa, most of them will develop resistance to ADT and progress to metastatic castration resistant prostate cancer (mCRPC). Constitutively transcriptional activated AR splice variants (AR-Vs) have emerged as critical players in the development and progression of mCRPC. Among AR-Vs identified to date, AR-V7 (a.k.a. AR3) is one of the most abundant and frequently found in both PCa cell lines and in human prostate tissues. Most of functional studies have been focused on AR-V7/AR3 and revealed its role in regulation of survival, growth, differentiation and migration in prostate cells. In this review, we will summarize our current understanding of regulation of expression and activity of AR-Vs in mCRPC.

Keywords: Androgen receptor; Metastatic castration; Prostate cancer; cancer; resistant prostate; splicing variants.

Figure 1

Proposed model of the role of AR-V7/AR3 in mCRPC. Upon androgen ablation, changes of genetic stability, transcription/splicing and epigenetic regulation alter the expression and activity of AR-V7. In addition to canonical AR–FL regulated genes, AR-V7 is able to regulate a subset distinct target genes to promote metastasis, cell survival and growth, and metabolic alteration in prostate cancer cells mCRPC: metastatic castration resistant prostate cancer.