When prostate cancer is first detected it generally is dependent on the presence of androgens for growth, and responds to androgen ablation therapies. However, the disease often recurs in a disseminated and apparently androgen independent (AI) form, and in this state is almost invariably fatal. Considerable evidence indicates that the Androgen receptor (AR) continues to be required even in androgen independent (AI) disease. Thus, a key to understanding hormone independent prostate cancer is to determine the mechanism(s) by which the AR can function even in the absence of physiologic levels of androgen. In this article, we argue that growth factors and receptors that utilize Ras family members drive prostate cancer progression to a state of androgen hypersensitivity; and that post-translational modifications (e.g., phosphorylations) of transcriptional cofactors might be responsible for modulating the function of the AR so that it is active even at low concentrations of androgen.
Copyright 2003 Wiley-Liss, Inc.