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.