Advanced prostate
tumors, which are
androgen dependent, are often initially treated in the clinic with
hormone ablation
therapy, either through surgical
castration or administration of small-molecule
antiandrogens. Most
tumors respond favorably to these treatments, exhibiting regression of the
tumor, amelioration of symptoms, and a decrease of
prostate-specific antigen in patient sera. However, with time, the majority of
tumors recur in a more aggressive,
castration-resistant (CR) phenotype. Currently, no effective treatment exists for this stage of the
cancer, and patients ultimately succumb to metastatic disease. The
androgen receptor (AR), which is a member of the
nuclear hormone receptor superfamily of
proteins, is the
transcription factor that is responsible for mediating the effects of
androgens upon target tissues, and it has been demonstrated to play a central role in the development and progression of
prostate cancer. Despite CR
tumor cells being able to continue to grow after hormonal
therapy in which
testosterone and
dihydrotestosterone are markedly reduced, they still require the expression and activity of the AR. The AR can become transactivated in this low-
androgen environment through a number of different mechanisms, including amplification and mutation of the receptor, cross talk with other signaling pathways, and altered regulation by coregulatory
proteins. This review will summarize the most current data regarding non-
ligand-mediated activation of the AR in
prostate cancer cells. Developing work in this field aims to more clearly elucidate the signals that drive AR activity independently of
androgens in CR disease so that better therapeutic targets can be developed for patients with this stage of highly aggressive prostate
carcinoma.