Role of the androgen receptor axis in prostate cancer.

Androgen receptor (AR) is expressed in nearly all prostate cancers, including treatment-refractory disease. The role of this receptor in the molecular endocrinology of prostate cancer has become increasingly clear in recent years. The AR is now known to participate in tumor progression through 3 mechanisms: expression (activation and upregulation of receptor activity), point mutations, and ligand-independent activation. With regard to the latter mechanism, interleukin-6 (IL-6) is among the most important nonsteroidal regulators of AR activity. In the absence of androgen, IL-6 causes activation of AR that is approximately 50% of the maximal activity induced by androgen. At low concentrations of androgen, IL-6 and androgen synergistically activate AR. Nonsteroidal antiandrogens usually antagonize this activation, but they switch to an agonist effect in the presence of oncostatin M, an IL-6-related cytokine. The growth of parental LNCaP cells is initially inhibited by exposure to IL-6, but long-term treatment renders the cells resistant to such inhibition and confers a growth advantage. Both IL-6 and oncostatin M stimulate AR activity, but only oncostatin M is associated with strong acquisition of the agonist properties of nonsteroidal antiandrogens. It is hoped that continuing research on AR expression and function in prostate cancer will pave the way for new therapeutic strategies.