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Objective: To assess the role of selected downstream Bcl-2 family members (Bad, Bax, Bcl-2 and Bcl-xL) in the development of androgen-independent prostate cancer (AIPC), as androgen-deprivation therapy is the treatment of choice in advanced prostate cancer, yet patients generally relapse and progress to an AI state within 18-24 months., Patients, Materials and Methods: The patient cohort was established by retrospectively selecting patients with prostate cancer who had an initial response to androgen-deprivation therapy, but subsequently relapsed with AIPC. In all, 58 patients with prostate cancer were included with matched androgen-dependent (AD) and AI prostate tumours available for immunohistochemical analysis; two independent observers using a weighted-histoscore method scored the staining. Changes in Bad, Bax, Bcl-2 and Bcl-xL expression during transition to AIPC were evaluated and then correlated to known clinical variables., Results: High Bad expression in AD tumours was associated with an increased time to biochemical relapse (P = 0.007) and a trend towards improved overall survival (P = 0.053). There were also trends towards a decrease in Bad (P = 0.068) and Bax (P = 0.055) expression with progression to AIPC. There were no significant results for Bcl-2 or Bcl-xL., Conclusion: There is evidence to suggest that Bad expression levels at diagnosis influence time to biochemical relapse and overall survival, and that levels of pro-apoptotic proteins Bad and Bax fall during AIPC development. Bad might therefore represent a possible positive prognostic marker and potential therapeutic target for AIPC in the future.

Molecular mechanisms underlying the development of androgen-insensitive prostate cancer (AIPC) are poorly understood. However, there is growing evidence that different molecular profiles may result in the development of AIPC. Cell line studies demonstrate that c-Jun and c-Fos, via formation of the transcription factor activated protein 1 (AP-1), activate androgen-regulated genes independent of androgens and that c-Jun alone acts as an androgen receptor co-factor. The aim of this study was to investigate whether increased levels of c-Jun and phosphorylated c-Jun are associated with the development of AIPC using clinical material. Material from a cohort of 51 patients with paired tumours, obtained before and after the development of AIPC, and with full clinical biochemical follow-up, was retrieved from the archives. Tumour c-Jun, activated c-Jun, c-Fos, and pan protein kinase C (PKC) protein expression were analysed by immunohistochemistry and protein expression was scored by two independent observers using a weighted histoscore. No evidence was found to suggest that c-Jun acting as an androgen receptor co-factor influences the development of AIPC. However, it was observed that patients with high expression levels of phosphorylated c-Jun had a significantly shorter survival from relapse compared with patients with low phosphorylated c-Jun protein expression (p = 0.023), suggesting that increased AP-1 levels may promote AIPC tumour growth. Whilst PKC did not appear to activate c-Jun in vivo, increased PKC expression in AIPC tumours was also associated with decreased patient survival from time of relapse (p = 0.014). In conclusion, the data support the hypothesis that activation of c-Jun plays a role in the development of AIPC via AP-1 formation in some patients. However, PKC appears to promote the development of AIPC independently of c-Jun activation via an as yet unexplained mechanism.