ANDROGEN-RECEPTOR GENE STRUCTURE AND FUNCTION IN PROSTATE-CANCER

Androgen-receptor (AR) gene mutations have been found in clinical pros tate cancer, both prior to hormonal therapy and in hormone-refractory disease that persists despite androgen-ablative therapy. Thus, mutatio ns that are present in late-stage disease might arise prior to therapy rather than as a result of therapy. A common feature of mutations in untreated prostate cancer and in hormone-refractory prostate cancer is that the AR retains activity as a ligand-dependent transcription fact or. Some AR mutations in prostate cancer show broadened ligand specifi city, such that the transcription-factor activity of the AR can be sti mulated not just by dihydrotestosterone (DHT) but also by estradiol an d other androgen metabolites that have a low affinity for the AR. The activation of mutant AR by estrogen and weak androgens could confer on prostate cancer cells an ability to survive testicular androgen ablat ion by allowing activation of the AR by adrenal androgens or exogenous estrogen. Such mutations might confer an advantage even prior to andr ogen ablation, since prostate cancer has lower levels of 5 alpha-reduc tase and, therefore, of DHT, than normal. Thus, AR mutations that occu r prior to therapy may characterize a more aggressive disease. A large percentage of tumors appear to have no AR gene mutation. In tumors wi thout an AR gene mutation, AR function might be affected via other mec hanisms (e.g., AR gene amplification, which could increase the amount of AR activity at a given DHT level). Importantly, the apparent absenc e of AR gene mutations in the majority of early-stage tumors indicates that the role of androgen in the development of clinical prostate can cer is mediated predominantly by a normal AR gene. There are actually multiple alleles of the normal AR gene; these allelic variants differ in glutamine and glycine repeat length in the transactivation domain o f the protein, and they may differ in signal-transducing activity. The glutamine and glycine repeat length may thereby modulate the effect o f androgen on tumor-cell proliferation that occurs during clonal expan sion.