Androgen Receptor Gene Mutations in Prostate Cancer. Implications for Disease Progression and Therapy

Recent studies indicate that androgen receptors are present in all histological types of prostatic tumours, in relapsed prostatic carcinomas and in tumour metastases, even those obtained from patients in whom endocrine therapy was unsuccessful. Several research groups have asked whether structurally altered androgen receptors might be present in human prostatic tumours. The first androgen receptor mutation in prostate cancer was detected in the tumour cell line LNCaP. The frequency of androgen receptor mutations in primary tumours of the prostate is relatively low. In contrast, a high frequency of mutations has been reported in bone metastases from patients who did not respond to endocrine therapy. This fact may reflect genetic instability in these late tumour stages. Mutant androgen receptors detected in human prostate cancer cells are 'promiscuous receptors'; that is, they are activated not only by synthetic and testicular androgens, but also by adrenal androgens, products of dihydrotestosterone metabolism, estrogenic and progestagenic steroids, and even by nonsteroidal antiandrogens. Interestingly, the nonsteroidal antiandrogens hydroxyflutamide and nilutamide, but not bicalutamide, have been reported to have agonistic effects at mutant androgen receptors. It is speculated that the existence of androgen receptor mutations may explain, at least in part, the 'antiandrogen withdrawal syndrome': a temporary improvement in a subpopulation of prostate cancer patients following cessation of an antiandrogen from a therapeutic protocol. Further studies on androgen receptor alterations in prostate cancer should focus on metastatic specimens obtained from the late stages of this disease.