The role of the androgen receptor in the development and progression of prostate cancer.

Androgens are essential for the development, growth, and maintenance of the prostate. They exert their effects via the intracellular androgen receptor (AR), which is a ligand-dependent transcription activator. As is the case with normal prostate development, primary prostatic cancers are largely dependent on androgens for growth and survival. Most patients respond favorably to androgen ablation and antiandrogen therapy, which has become a standard treatment of metastatic disease. However, virtually all patients will relapse with clinically defined androgen-independent cancer. This phenomenon raises the question of how cancer cells survive and grow in the low androgen environment? Two of the routes cells can take to adapt are (1) bypassing and (2) sensitizing the AR pathway. The vast numbers of AR abnormalities observed in prostate tumors from patients treated with hormonal therapy suggest that many cells sensitize or change the AR pathway. To continue to activate this pathway in a low androgen environment, cells can (1) mutate the AR to become promiscuously activated by different steroids, (2) amplify the AR, (3) activate the AR in a ligand-independent manner by growth factors and cytokines, or (4) amplify coactivators. Alternatively, prostate cancer cells that have lost AR expression must have bypassed the AR pathway. Activation of oncogenes and autocrine growth factor stimulation are two mechanisms that likely contribute to becoming completely androgen-independent. From all the studies on AR function in prostate cancer, it is clear that the AR plays an important role in cancer development and progression. Moreover, the AR pathway remains important in most cells from patients with clinically defined androgen-independent prostate cancer.