Androgen receptor signaling in prostate cancer development and progression

Abstract

The androgen receptor (AR) signaling axis plays a critical role in the development, function and homeostasis of the prostate. The classical action of AR is to regulate gene transcriptional processes via AR nuclear translocation, binding to androgen response elements on target genes and recruitment of, or crosstalk with, transcription factors. Prostate cancer initiation and progression is also uniquely dependent on AR. Androgen deprivation therapy remains the standard of care for treatment of advanced prostate cancer. Despite an initial favorable response, almost all patients invariably progress to a more aggressive, castrate-resistant phenotype. Considerable evidence now supports the concept that development of castrate-resistant prostate cancer (CRPC) is causally related to continued transactivation of AR. Understanding the critical events and complexities of AR signaling in the progression to CRPC is essential in developing successful future therapies. This review provides a synopsis of AR structure and signaling in prostate cancer progression, with a special focus on recent findings on the role of AR in CRPC. Clinical implications of these findings and potential directions for future research are also outlined.

Keywords: Androgen receptor; castrate-resistant prostate cancer; signaling.

Figure 1

Schematic representation of the androgen receptor gene and protein, with indications of its specific motifs and domains

Figure 2

Summary of the major androgen receptor signaling pathways in prostate cancer. Upon binding to dihydrotestosterone, androgen receptor translocates to the nucleus, binds to its target genes and regulates their expression. Androgen receptor can also be transactivated in the absence, or in very low levels of dihydrotestosterone. Activating signals arise from several, non-mutually-exclusive mechanisms including extracellular peptides such as Insulin-like growth factor, Epidermal growth factor and Interleukin-6