Androgen receptor biology in prostate cancer

Androgens are essential development and survival factors for prostate epithelial cells. Prostate cancer cells retain androgen dependence and, for some period of time, are suppressed by androgen deprivation. Castration-resistant prostate cancer (CRPC) arises after a period of androgen withdrawal and represents the most advanced stage of the disease. CRPC is mediated by the reactivation of androgen receptor activity in the castrate patient. Androgen receptor is reactivated in CRPC by a variety of mechanisms, the breadth of which underscores the importance of androgen receptor for prostate cancer cell proliferation at all stages of the disease. Androgen receptor gene may be affected by the amplification of the locus on the X chromosome or by the activation of mutations. Androgen receptor protein may be phosphorylated by a variety of kinases to enhance its activity in the presence of subphysiologic concentrations of ligand. The cancer cells themselves may produce sufficient levels of androgenic steroids to sustain receptor activation. Androgen receptor activity may also be enhanced by the overexpression of coactivator proteins that allow the formation of the transcriptional complex after the androgen receptor binds to DNA. Lastly, androgen receptor mRNA may be subjected to alternative splicing that may generate ligand-independent truncated forms of activated androgen receptor protein. Thus CRPC cells reactivate androgen receptor as a critical pathway towards cancer progression.