Abstract 2251: Functional significance of prostate derived ETs factor in detection of highgrade prostate cancer

Abstract

Abstract INTRODUCTION AND OBJECTIVES: Conventional therapies produce a high rate of cure for patients with localized prostate cancer, but there is, at present, no effective treatment for intervention in metastatic prostate cancer. These facts underline the need to develop new approaches for early diagnosis of aggressive prostate cancer patients, and mechanism based anti-metastasis therapies that will improve the outlook for hormone-refractory prostate cancer. In this study we evaluated role of prostate-derived Ets factor (PDEF) in prostate cancer. METHODS: PDEF and MMP9 expression was assayed by Immuno-histochemical methods in Prostate Cancer tissue microarrays. PDEF expression in cell lines was investigated using Western Blot analysis. We constructed cells with stable expression of PDEF using a retroviral vector or knocked down PDEF in cells using PDEF specific SiRNA. Cell migration, invasion and clonogenic activity were monitored using scratch assays, Matrigel invasion assays and growth in soft agar respectively. RESULTS: We observed decrease of PDEF expression in prostate cancer cell lines correlated with increased aggressive phenotype, and complete loss of PDEF protein in metastatic prostate cancer cell lines. Loss of PDEF expression was confirmed in high Gleason Grade prostate cancer samples by immunohistochemical methods. Our results also demonstrated that PDEF down regulated MMP-9 promoter activity, suppressed MMP9 mRNA expression, and resulted in loss of MMP9 activity in prostate cancer cells. These results suggested that loss of PDEF might be associated with increased MMP9 expression and activity in aggressive prostate cancer. To confirm results we investigated MMP9 expression in clinical samples of prostate cancer. Results of these studies show increased MMP9 expression correlated with advanced Gleason grade. Taken together our results demonstrate that decreased PDEF expression and increased MMP-9 expression during the transition to aggressive prostate cancer. CONCLUSIONS: These studies demonstrate for the first time negative regulation of MMP9 expression by PDEF, that PDEF expression was lost in aggressive prostate cancer and was inversely associated with MMP-9 expression in clinical samples of prostate cancer. Based on these exciting results we propose that loss of PDEF along with increased MMP9 expression should serve as novel markers for early detection of aggressive prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2251.