Abstract 967: Serine proteases as targets for prostate cancer prevention: Identification by analysis of differential gene expression in rodent and human prostate cancers

Abstract

Abstract Patterns of gene expression in normal and neoplastic prostate tissues from rats and humans were compared to identify novel molecular targets for prostate cancer chemoprevention. Differentially expressed genes in human prostate cancers were identified by reviewing published genome-wide screening studies and hypothesis-driven studies of gene expression in prostate cancer patients. Differentially expressed genes in rat prostate cancers were identified by microarray analysis (using Affymetrix Rat 230 2.0 GeneChips) of paired malignant and phenotypically normal prostatic tissues harvested from Wistar-Unilever rats treated with N-methyl-N-nitrosourea [MNU] + testosterone. Patterns of differential gene expression in human prostate cancers demonstrated only limited concordance between studies in clinical populations performed by different groups. Most differentially expressed genes were identified in only a single human study; only two genes (AMACR [α-methylacyl-CoA racemase] and HPN [hepsin, a protease inhibitor]) were found to be differentially expressed in >25% of the human prostate cancer microarray studies evaluated. Genes found to be differentially expressed in multiple hypothesis-driven studies of human prostate cancers included E2F1 (transcription factor), MUC1 (mucin 1), PLAB (placental bone morphogenetic protein), and ST14 (serine protease); these genes were not identified in genome-wide screening studies of human prostate cancers. In tissues harvested from rats treated with MNU + testosterone, 890 genes were identified as differentially regulated (fold change > 1.5 and p < 0.001) in prostate cancers in comparison to paired phenotypically normal prostate tissues. These 890 genes included four serine protease genes (Prss 11, Prss22, Prss 25, and Prss35) that were significantly up-regulated (by 1.7 to 11.4-fold). In addition, five serine protease inhibitor genes (Serpins e1, e2, f1, g1, h1) were over-expressed in rat prostate cancers (by 2.2 to 23.5-fold), suggesting possible up-regulation in response to increased protease activity in prostatic neoplasms. When human and rat gene expression data are considered together, serine proteases were the only class of molecules that demonstrated a reproducible pattern of differential gene expression in prostate cancers in both species. These data suggest that modulation of protease activity may provide a useful target for prostate cancer prevention. This conclusion is supported by our finding that Bowman-Birk Inhibitor, a mixture of soy-based protease inhibitors, inhibits carcinogenesis in the rat prostate (Nutr. Cancer, 57, 184, 2007). Development of small molecule protease inhibitors may be a useful strategy for prostate cancer chemoprevention. (Supported by IR&D funds from IIT Research Institute, NCI-N01-CN-25017, and NCI-N01-CN-85177) 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 967.