ANDROGEN RECEPTOR GENE AMPLIFICATION - A POSSIBLE MOLECULAR MECHANISMFOR ANDROGEN DEPRIVATION THERAPY FAILURE IN PROSTATE-CANCER

Progression of prostate cancer during endocrine therapy is a major cli nical problem, the molecular mechanisms of which remain poorly underst ood, Amplification of the androgen receptor (AR) gene was recently des cribed in recurrent prostate carcinomas from patients who had failed a ndrogen deprivation therapy, To evaluate the hypothesis that amplifica tion of the AR gene is a cause for the failure of androgen deprivation therapy in prostate cancer, we studied whether AR amplification leads to gene overexpression, whether the amplified AR gene is structurally intact, and whether tumors with AR amplification have distinct biolog ical and clinical characteristics. Tumor specimens were collected from 54 prostate cancer patients at the time of a local recurrence followi ng therapy failure, In 26 cases, paired primary tumor specimens from t he same patients prior to therapy were also available, Fifteen (28%) o f the recurrent therapy-resistant tumors, but none of the untreated pr imary tumors, contained AR gene amplification as determined by fluores cence in situ hybridization. According to single-stranded conformation polymorphism analysis, the AR gene was wild type in all but one of th e 13 AR amplified cases studied, In one tumor, a presumed mutation in the hormone-binding domain at codon 674 leading to a Gly --> Ala subst itution was found, but functional studies indicated that this mutation did not change the transactivational properties of the receptor, AR a mplification was associated with a substantially increased level of mR NA expression of the gene by in situ hybridization. Clinicopathologica l correlations indicated that AR amplification was most likely to occu r in tumors that had initially responded well to endocrine therapy and whose response duration was more than 12 months, Tumors that recurred earlier or those that shelved no initial therapy response did not con tain AR amplification, The median survival time after recurrence was t wo times longer for patients with AR amplification in comparison to th ose with no amplification (P = 0.03, Willcoxon-Breslow test), In concl usion, failure of conventional androgen deprivation therapy in prostat e cancer may be caused by a clonal expansion of tumor cells that are a ble to continue androgen-dependent growth despite of the low concentra tions of serum androgens, Amplification and the increased expression o f a wild-type AR gene may play a key role in this process.