Abstract 818: Modulation of gene expression and cell cycle signaling pathways in Iressa-treated urinary bladder cancer in rats

Abstract

Abstract The EGFR inhibitor Iressa has demonstrated strong preventive efficacy in the N-butyl-N-(4-hydroxybutyl)-nitrosamine (OH-BBN) model of bladder cancer in the rat. To explore its antitumor mechanism, we implemented a systems biology approach to characterize gene expression and signaling pathways in rat urinary bladder cancers treated with Iressa. Eleven bladder tumors from control rats, seven tumors from rats treated with Iressa and seven normal bladder epithelia were profiled using Affymetrix Rat Exon 1.0 ST Arrays. We identified 713 down-regulated and 641 up-regulated genes in comparing bladder tumors vs. normal bladder epithelia. In addition, 178 genes were down-regulated and 96 genes were up-regulated when comparing control tumors vs. Iressa-treated tumors. Two coexpression modules that were significantly correlated with tumor status and treatment status were identified (r = 0.70, P = 2.80 × 10−15 (bladder tumor vs. normal bladder epithelium) and r = 0.63, P = 2.00 × 10−42 (Iressa-treated tumor vs. control tumor), respectively). Both tumor module and treatment module were enriched for genes involved in cell cycle processes. Twenty-four and twenty-one highly connected hub genes likely to be key drivers in cell cycle were identified in the tumor module and treatment module, respectively. Analysis of microRNA genes on the array chips demonstrated that tumor module and treatment module were significantly associated with expression levels of let-7c (r = 0.54, P = 3.70 × 10−8 and r = 0.73, P = 1.50 × 10−65 respectively). These results suggest that let-7c down-regulation and its regulated cell cycle pathway may play an integral role in governing bladder tumor suppression or collaborative oncogenesis and that Iressa exhibits its preventive efficacy on bladder tumorigenesis by up-regulating let-7 and inhibiting the cell cycle. The identified hub genes may also serve as pharmacodynamic or efficacy biomarkers in clinical trials of chemoprevention in human bladder cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 818. doi:10.1158/1538-7445.AM2011-818