Androgens, antiandrogens and androgen receptor abnormalities

Information on the molecular structure of the human androgen receptor has increased insight into the molecular mechanism of action of androgens and antiandrogens. It has also facilitated the study of molecular defects in the androgen receptor gene associated with prostate cancer. Several somatic mutations have been detected in tumour specimens of patients with prostate cancer. Most of the reported mutations are localised in the ligand binding domain. A relatively high frequency of the Thr868Ala mutation (originally reported for the human prostate cancer cell line androgen receptor) is particularly found in metastatic lesions (bone metastases) of prostate cancer and can be considered as a hot spot. It could be speculated that this specific mutant androgen receptor provides a selective growth advantage in a subset of advanced prostate cancers. For a limited number of mutations it has been shown that ligand responsiveness to adrenal androgens, progestagens, oestrogens and some antiandrogens of the mutant receptors has been increased. The consequences of these mutations could be that the androgen receptor can still be activated in castrated patients and during antiandrogen therapy. The observation, therefore, that antiandrogen withdrawal can be beneficial for some prostate cancer patients, might be understood in the light of an altered ligand responsiveness of mutant androgen receptors.