Co-assessment of cytoplasmic and nuclear androgen receptor location in prostate specimens: potential implications for prostate cancer development and prognosis.

OBJECTIVE: To address, by co-assessing cytoplasmic and nuclear androgen receptor (AR) expression in prostate tissues, the contribution of the AR throughout the stages of prostate cancer (PC) and its value as a marker for predicting biochemical recurrence (BCR) after radical prostatectomy (RP). PATIENTS AND METHODS: Archival prostate specimens from patients who were cancer-free (43), with hormone-sensitive prostate cancer (HSPC, 62), and with androgen-independent prostate cancer (AIPC, 30) were used to construct tissue microarrays (total 135). Prostatic intraepithelial neoplasia (PIN) and non-neoplastic tissues (NA) found adjacent to HSPC were also included. Nuclear and cytoplasmic AR expression was scored by two observers using a composite scale, after immunohistochemical detection of the AR. The nuclear/cytoplasmic AR expression ratio was also calculated. Univariate Kaplan-Meier plots, and multivariate Cox and survival-tree analyses, were then used to assess the ability of the AR to predict BCR in the patients with HSPC. RESULTS: There was markedly greater nuclear AR staining intensity in NA than in normal prostate tissues from cancer-free patients. Cytoplasmic AR expression was highest in AIPC and markedly more than in HSPC. The nuclear/cytoplasmic AR expression ratio was highest in NA and PIN. In univariate analyses, a low nuclear AR, low cytoplasmic AR, and a high nuclear/cytoplasmic AR expression ratio were associated with BCR. Although cytoplasmic AR was an independent predictor of BCR in a Cox multivariate model (hazard ratio 2.736, 95% confidence interval 1.228-6.091, P = 0.014), survival-tree analyses suggested a complex relationship between AR expression and clinicopathological features. CONCLUSION: We propose that increased nuclear AR expression might be a precursor to PC and that cytoplasmic AR could contribute to the AIPC phenotype. The predictive ability of the AR might be closely linked to clinicopathological features.

NOXA and PUMA expression add to clinical markers in predicting biochemical recurrence of prostate cancer patients in a survival tree model.

PURPOSE: To assess the expression of proapoptotic NOXA and PUMA in prostate tissues and delineate their association with prostate cancer (PCa) recurrence. EXPERIMENTAL DESIGN: Normal, prostatic intraepithelial neoplasia (PIN), hormone-sensitive (HS) PCa, and hormone-refractory (HR) PCa tissues were used to build tissue microarrays encompassing a total of 135 patients. Two observers assessed the intensity of NOXA and PUMA immunohistochemical staining using a composite color scale. One hundred and eighty recursive partitioning and regression tree (RPART) models were generated to predict biochemical recurrence (BCR) within HS cancer patients using NOXA, PUMA, and clinical parameters. Models were then ranked according to the integrated Brier score (IBS). RESULTS: Increasing NOXA expression was associated with PCa progression, reaching the highest levels in HR PCa. Increased NOXA expression was observed in 68% of HS cancer patients and was predictive of BCR (LR = 8.64; P = 0.003). In contrast, PUMA expression was highest in HS cancer, and although 70% of HS cancer patients exhibited increased PUMA expression, PUMA alone could not predict the onset of BCR. Interestingly, the top-ranking RPART model generated [IBS = 0.107; 95% confidence interval (95% CI), 0.065-0.128] included surgical margin status and NOXA and PUMA expression, although recurrent prognostic classification schemes obtained in the top 10 models favored a survival tree model containing margin status, NOXA expression, and preoperative prostate-specific antigen (PSA) (IBS = 0.114; 95% CI, 0.069-0.142). CONCLUSION: We conclude that NOXA and PUMA expression may be linked to PCa progression and propose further validation of a survival tree model including surgical margin status, NOXA expression, and preoperative PSA for predicting BCR.