Decoding the androgen receptor splice variants

In the past five years, multiple structurally and functionally distinct androgen receptor (AR) splice variants have been decoded and characterized. The mature transcripts for the majority of the fully decoded AR splice variants contain a transcribed "intronic" sequence, capable of encoding a short variant-specific peptide to replace the AR ligand-binding domain (LBD). Functionally, AR splice variants represent a diverse group of molecules often demonstrating cell context-specific genomic functions that may or may not be coupled with the functions of the canonical full-length AR (AR-FL). However, the full spectrum of their functional diversity and the underlying mechanistic basis remains very poorly characterized. In clinical specimens derived from men treated with a variety of hormone therapy regimens, AR splice variants are almost always expressed at detectable, yet lower levels when compared to that of AR-FL. In spite of the collective in vitro data supporting the putative role of AR splice variants in therapeutic resistance to hormone therapies, the extent to which AR splice variants mediate resistance to each individual regimen is not known and awaits thorough investigations in a clinically relevant setting using specimens from men undergoing treatments. Among the AR splice variants, AR-V7 is more abundantly and frequently expressed in castration-resistant prostate cancer (CRPC) and remains the most important variant identified so far. The relative importance of different AR molecules, including AR-FL, should be functionally dissected in the setting of castration-resistant prostate cancer, particularly in tumors resistant to more potent inhibitors of AR-FL recently approved by the FDA. In this review, we will focus on the discovery and characterization of AR splice variants, their putative functions and roles in mediating constitutively active AR signaling, and key areas of investigation that are necessary to establish their clinical relevance.