PUMA and NOXA Expression in Tumor-Associated Benign Prostatic Epithelial Cells Are Predictive of Prostate Cancer Biochemical Recurrence

Abstract

Simple SummaryAfter receiving a diagnosis of prostate cancer, patients follow a routine treatment plan based on tumor grade, stage and prostate-specific antigen (PSA) level. However, studies in other cancers have shown the importance of using biomarkers to personalize treatments. With no approved biomarkers presently in use in prostate cancer, there is a clinical need to develop such stratification tools. Here our study shows that PUMA and NOXA are markers that have a high prognostic value when looking at their presence in both benign and tumor glands within the prostate. Hence, the presence of these markers may help to better predict outcomes at diagnosis. Incorporating these markers into clinical practice may eventually lead to selective treatment options in newly diagnosed patients. This in turn should lead to better cancer control, potentially lowering the morbidity and mortality due to prostate cancer.Background: Given that treatment decisions in prostate cancer (PC) are often based on risk, there remains a need to find clinically relevant prognostic biomarkers to stratify PC patients. We evaluated PUMA and NOXA expression in benign and tumor regions of the prostate using immunofluorescence techniques and determined their prognostic significance in PC. Methods: PUMA and NOXA expression levels were quantified on six tissue microarrays (TMAs) generated from radical prostatectomy samples (n = 285). TMAs were constructed using two cores of benign tissue and two cores of tumor tissue from each patient. Association between biomarker expression and biochemical recurrence (BCR) at 3 years was established using log-rank (LR) and multivariate Cox regression analyses. Results: Kaplan–Meier analysis showed a significant association between BCR and extreme levels (low or high) of PUMA expression in benign epithelial cells (LR = 8.831, p = 0.003). Further analysis revealed a significant association between high NOXA expression in benign epithelial cells and BCR (LR = 14.854, p < 0.001). The combination of extreme PUMA and high NOXA expression identified patients with the highest risk of BCR (LR = 16.778, p < 0.001) in Kaplan–Meier and in a multivariate Cox regression analyses (HR: 2.935 (1.645–5.236), p < 0.001). Conclusions: The combination of PUMA and NOXA protein expression in benign epithelial cells was predictive of recurrence following radical prostatectomy and was independent of PSA at diagnosis, Gleason score and pathologic stage.