Evolving roles for the androgen receptor and its protein interactome in castration-resistant prostate cancer

Abstract The androgen receptor (AR) is a ligand-activated transcription factor that is a major driver of lethal prostate cancer (CaP) progression. Androgen deprivation therapy (ADT) that prevents the binding of androgens to AR has been the mainstay for the treatment of non-organ-confined CaP for more than 8 decades. Although ADT initially induces remissions, eventually resistance occurs while the majority of castration-resistant CaPs (CRPCs) continue to rely on AR’s action for growth. Sustained AR-dependence of CaP that recurs under ADT has historically been linked to AR’s transcriptional activity that controls expression of a distinct program of target genes that mediate aggressive behavior. Recently, less traditional transcriptional roles for AR, such as those impacting non-coding RNAs as well as transcription-independent roles that include AR-dependent splicing programs and translation control have been recognized to contribute to aggressive CaP features and treatment resistance. We reviewed and contrasted the contribution and relevance of these distinct functions for AR during CaP progression. We also considered the roles therein, both overlapping or mutually exclusive, for functionally diverse AR-interacting proteins that have been identified and to date have been mostly considered AR-associated transcriptional regulators. We discuss the potential implications of the involvement of AR interactors in multiple AR-dependent (non-)transcriptional cellular processes for alternative CaP treatment strategies that disrupt AR-coregulator interplay to inhibit AR-dependent transcription when AR ligand-deprivation has failed.