Amplification of the androgen receptor may not explain the development of androgen‐independent prostate cancer

Abstract

Objective To examine the role of androgen receptor (AR) gene amplification and aneusomy of the X chromosome in the development of antiandrogen‐resistant prostate cancer. Patients and methods Twenty patients with prostate cancer resistant to androgen‐deprivation therapy were selected for study. The records of patients with tumours before and after antiandrogen therapy, and with a full clinical follow‐up, were retrieved. AR gene amplification and X chromosome copy number were assessed by fluorescence in situ hybridization using a labelled probe at locus Xq11–13 for the AR gene and a labelled α‐satellite probe for the X chromosome. At least 20 nuclei were scored over three tumour areas by two independent observers. Results Aneusomy of the X chromosome was reported respectively in seven (35%) and 11 (55%) tumours before and after hormone relapse, the AR gene copy number was increased in seven (35%) and 13 (65%), respectively, and AR gene amplification was detected in one (5%) and three (15%), respectively. Neither increased AR copy number nor AR amplification in primary tumours precluded a biological response to androgen‐deprivation therapy. Conclusion The rate of AR gene amplification is too low to be solely responsible for the development of antiandrogen‐resistant prostate cancer. Also, the presence of amplified AR and cells aneusomic for the X chromosome in primary tumours that respond to androgen‐deprivation therapy suggests that an increase in AR gene copy number does not prevent a tumour from responding to this therapy. Therefore other mechanisms which could cause hormone‐refractory prostate cancer must be investigated before it is understood why so many patients relapse with this disease.

Amplification and protein expression of androgen receptor gene in prostate cancer cells: Fluorescence in situ hybridization analysis

“…The number of AR gene signals and X centromere signals was evaluated by visual analysis of 800 to 1,200 nuclei per specimen. AR amplification was present if the AR to X ratio exceeded 1.5 (14), and X polysomy was present if the number of X centro mere signals exceeded an average of 2 signals per cell (15).…”

Phosphorylation of the androgen receptor is associated with reduced survival in hormone-refractory prostate cancer patients

“…Amplification of the androgen receptor (AR) may explain development of HRPC in 20 -30% of patients (Edwards et al, 2001). In vitro studies demonstrate that Akt/protein kinase B phosphorylates AR at serine residues (Ser 210 and Ser 790 ) resulting in modulation of AR transcriptional activity (Lin et al, 2001(Lin et al, , 2003 and suggesting that AR phosphorylation might promote development of HRPC.…”

Proteomic analysis of androgen-independent growth in low and high passage human LNCaP prostatic adenocarcinoma cells

“…Therefore, AR is a key target for the treatment of both early stage PCa, and the inactivation of AR expression should be an important approach for the successful treatment of hormone-refractory PCa. However, alteration of ARs might not fully explain the conversion to the hormone refractory state in PCa (27). Indeed, reports have described an androgen response in LNCaP cells, although these have resulted in few protein identifications responsible for the progression of LNCaP cell line to hormone-insensitive stage (20,21).…”

“…Indeed, reports have described an androgen response in LNCaP cells, although these have resulted in few protein identifications responsible for the progression of LNCaP cell line to hormone-insensitive stage (20,21). Moreover, one study sought to identify differentially expressed proteins in human prostate tissue with particular interest in the proteins lost in malignancy (27). As an initial step towards discriminating the candidate proteins responsible for tumorigenic progression in LNCaP cells, we used a proteomic approach based on 2-DE separation followed by identification with MALDI-TOF MS to study changes in the global expression pattern.…”