Androgen Signaling in Prostate Cancer

The androgen-signaling axis plays a pivotal role in the pathogenesis of prostate cancer. Since the landmark discovery by Huggins and Hodges, gonadal depletion of androgens has remained a mainstay of therapy for advanced disease. However, progression to castration-resistant prostate cancer (CRPC) typically follows and is largely the result of restored androgen signaling. Efforts to understand the mechanisms behind CRPC have revealed new insights into dysregulated androgen signaling and intratumoral androgen synthesis, which has ultimately led to the development of several novel androgen receptor (AR)-directed therapies for CRPC. However, emergence of resistance to these newer agents has also galvanized new directions in investigations of prereceptor and postreceptor AR regulation. Here, we review our current understanding of AR signaling as it pertains to the biology and natural history of prostate cancer.