The androgen/androgen receptor axis in prostate cancer

Abstract

Purpose of review: The review highlights recently discovered mechanisms that sustain castration-resistant prostate cancer (CRPC) growth and describes advances in CRPC therapeutics.

Recent findings: Recent reports have shed new light on the molecular processes underlying CRPC survival during androgen deprivation therapy (ADT). This study summarizes recent findings and comments on their clinical relevance. Included in this review is a discussion on molecular mechanisms that regulate androgen receptor (AR) signaling in normal prostate epithelium and CRPC, biologically significant differences in the androgen-regulated transcriptional programs of androgen-dependent prostate cancer and CRPC, and recent discoveries involving de-novo androgen production and transport. We review the status and results of current clinical trials and finally, discuss the implications of evidence suggesting a declining importance of AR signaling in prostate cancers with PTEN loss.

Summary: Advances in the understanding of AR signaling in CRPC have identified novel drug targets and improved the rational design of targeted therapy, while illuminating a subset of prostate cancers that may progress to become completely independent of the AR signaling program.

Figure 1

Mechanisms of AR pathway activation in CRPC. 1) AR gene amplification. 2) Rb increases E2F1 activity and AR transcription. 3) Low AR activity leads to increased AR expression via an enhancer element. Increased AR transcriptional activity recruits LSD1 to exert negative feedback on this pathway. 4) mRNA splicing generates LBD-deficient AR variants. 5) Extra-testicular ligand production maintains AR transcriptional activity. 6) ARVs induce ligand-independent expression of ARGs. ARG* represents the differential transcription program activated by some ARVs. 7) AR cofactors, such as NCOA2, amplify the magnitude of AR signaling.

Figure 2

Feedback pathways of AR, PTEN, and PI3K. AR transcriptional activity represses PI3K signaling through the expression of FKBP5. FKBP5 facilitates the dephosphorylation of AKT by PHLPP. PTEN loss, common in prostate cancer, increases PI3K pathway activity and may also repress AR. Two prominent hypotheses explaining the mechanism of PI3K activity and AR repression are presented. 1) Carver et al hypothesize that HER kinases induce expression of AR, and increased PI3K signaling inhibits HER kinases in an mTOR-dependent fashion. This decreases AR expression [28**]. 2) Mullholland et al propose a mechanism by which PTEN negatively regulates the expression and activity of a number of proteins that modulate AR activity (EZH2, JUN, EGR1). PTEN loss deregulates these proteins, repressing AR expression [27**]. Dashed lines indicate pathways where activity is downregulated by PTEN loss.