Abstract A108: Differential expression of peroxiredoxins in prostate cancer: Ethnic differences in the association of PRDX3 expression with clinical outcomes

Abstract Prostate cancer (PCa) is the most frequently diagnosed male cancer and the second leading cause of cancer death in men in the United States. This growing public health challenge is aggravated by disparities in the incidence and mortality of PCa among African-American (AA) men, compared to Caucasian (CC) men and other ethnic groups. The reasons for these disparities are not completely understood, although available evidence points to the convergence of multiple, interrelated factors, such as socioeconomics, unequal access to health care and screening, unhealthy lifestyle and diet, ancestry, and genetic susceptibility. Emerging evidence suggests that chronic inflammation of the prostate contributes to PCa development by inducing oxidative molecular damage, which in turns lead to the upregulation of stress and redox proteins that protect tumor cells against apoptosis and therapeutic interventions. Evaluation of the expression and role of these proteins in prostate tumors from different ethnic populations would help define molecular and cellular factors associated with prostate tumor aggressiveness and therapy resistance, and uncover potential biological determinants of PCa health disparities. The peroxiredoxin (PRDX) protein family consists of six anti-oxidant enzymes (PRDX1-6) that are emerging as key regulators of cellular anti-oxidant defense, and are being increasingly implicated in malignant transformation and therapy resistance. Very little is known about their role in prostate cancer. In this study we investigated their expression and association with clinical outcomes in prostate cancer (PCa). The expression of PRDX1-6 in PCa was evaluated in 14 cancer gene microarray datasets (from Oncomine and SPECS), by immunoblotting in a panel of 11 prostate cell lines, and by immunohistochemistry (IHC) in prostate tissue microarrays (TMA) containing tumor (n=80) and control (n=17) tissues. PRDX3 was also analyzed in TMA containing PCa tissues from AA and CC patients (n=150 per group). PRDX expression was correlated with patients’ clinicopathologic characteristics. Analysis of PRDX expression in cancer microarray databases revealed consistent upregulation (tumor vs normal) of PRDX3 and 4. All PRDXs exhibited elevated protein expression in PCa cell lines, compared with non-tumor cells. IHC revealed significant overexpression of PRDX3 and 4 in PCa, associated with increased prostate specific antigen (PSA), tumor stage, or Gleason score. High PRDX3 expression was associated with early age and elevated Gleason score at time of radical prostatectomy in AA but not in CC patients with PCa. PSA recurrence free survival in patients with low PRDX3 tumor expression was significantly longer in CC compared to AA patients, but no difference was detected for high expression. We conclude that PRDXs exhibit differential expression in prostate tumors, with PRDX3 and 4 consistently upregulated. The role of these two proteins in PCa development, and their potential as biological determinants of PCa health disparities and novel therapeutic targets, deserve further investigation. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):A108.