Androgen action in the prostate gland

Abstract

The embryonic development, growth and maturation of the prostate relies on androgens, the male sex steroids, acting through their cognate receptor, the androgen receptor (AR). This dependence on androgens continues in adult life, where AR signaling remains necessary for the maintenance of the structural and functional integrity of the prostate gland. Moreover, AR action contributes to the development and progression of prostate cancer (PCa), which is the most common malignancy in Western men. Androgen deprivation therapies (ADTs) that interfere with ligand activation of AR to prevent expression of AR target genes and androgen action on target cells have been the standard therapy for locally advanced or recurrent PCa for 7 decades. While they initially induce remission, ADTs are not curative and eventually PCa recurs as castration-recurrent (CR) disease, which is invariably lethal. Despite low levels of circulating androgens, CR PCa cell proliferation still relies on a functional AR. Recently, new insights into the cellular processes and determinants that regulate AR action, including intraprostatic androgen metabolism, AR structure and function, a novel role for well-known tumor suppressors and oncogenes in the control of AR transcriptional output, unexpected non-transcriptional roles for AR, and the identification of distinct modes of androgen-dependent gene expression, have enhanced markedly our understanding of the AR-dependent events that contribute to progression to the lethal stage of PCa. Here, we provide a general overview of androgen action in prostate (cancer), summarize these novel concepts in AR action and discuss their implications for the optimization of therapeutic intervention in PCa.