Purpose: Colon cancer is a major cause of cancer deaths. Dietary factors contribute substantially to the risk of this malignancy. Western-style diets promote development of azoxymethane-induced colon cancer. Although we showed that epidermal growth factor receptors (EGFR) controlled azoxymethane tumorigenesis in standard fat conditions, the role of EGFR in tumor promotion by high dietary fat has not been examined. Experimental Design: A/J × C57BL6/J mice with wild-type Egfr (Egfr wt ) or loss-offunction waved-2 Egfr (Egfr wa2 ) received azoxymethane followed by standard (5% fat) or western-style (20% fat) diet. As F 1 mice were resistant to azoxymethane, we treated mice with azoxymethane followed by one cycle of inflammation-inducing dextran sulfate sodium to induce tumorigenesis. Mice were sacrificed 12 weeks after dextran sulfate sodium. Tumors were graded for histology and assessed for EGFR ligands and proto-oncogenes by immunostaining, Western blotting, and realtime PCR. Results: Egfr wt mice gained significantly more weight and had exaggerated insulin resistance compared with Egfr wa2 mice on high-fat diet. Dietary fat promoted tumor incidence (71.2% versus 36.7%; P < 0.05) and cancer incidence (43.9% versus 16.7%; P < 0.05) only in Egfr wt mice. The lipid-rich diet also significantly increased tumor and cancer multiplicity only in Egfr wt mice. In tumors, dietary fat and Egfr wt upregulated transforming growth factor-α, amphiregulin, CTNNB1, MYC, and CCND1, whereas PTGS2 was only increased in Egfr wt mice and further upregulated by dietary fat. Notably, dietary fat increased transforming growth factor-α in normal colon. Conclusions: EGFR is required for dietary fat-induced weight gain and tumor promotion. EGFR-dependent increases in receptor ligands and PTGS2 likely drive diet-related tumor promotion. (Clin Cancer Res 2009;15(22):6780-9)

Purpose: Colonic carcinogenesis deranges growth-regulating epidermal growth factor receptors (EGFR). We previously showed that EGFR signals were up-regulated in human aberrant crypt foci (ACF), putative colon cancer precursors. The azoxymethane model of colon cancer recapitulates many aspects of human colonic tumors. Recent studies indicate that flat dysplastic ACF with increased h-catenin are tumor precursors in this model. We asked, therefore, if EGFR signals are required for flat dysplastic ACF development and cancer progression. Experimental Design: Rats received azoxymethane or saline, and standard chow or chow supplemented with gefitinib, an EGFR inhibitor, for 44 weeks. EGFR signals were quantified in normal colon, flat ACF, and tumors by computerized analysis of immunostains and Western blots. K-ras mutations were assessed by PCR and mRNA for egfr ligands by quantitative real-time PCR. Results: EGFR inhibition with gefitinib decreased the incidence of flat dysplastic ACF from 66% to 36% and tumors from 71% to 22% (P < 0.05). This inhibitor also reduced the overexpressions of cyclin D1 and Cox-2 in flat ACF. Furthermore, in flat ACF, EGFR blockade decreased the upregulation of c-Jun, FosB, phosphorylated active signal transducers and activators of transcription 3, and CCAAT/enhancer binding protein-h, potential regulators of cyclin D1 and Cox-2. In colonic tumors, EGFR blockade significantly decreased angiogenesis, proliferation, and progression while also increasing apoptosis (P < 0.05). Gefitinib also inhibited the activations of extracellular signal^regulated kinase, Src, and AKT pathways in tumors. Conclusions: We have shown for the first time that EGFR promotes the development of flat dysplastic ACF and the progression of malignant colonic tumors. Furthermore, we have mechanistically identified several transcription factors and their targets as EGFR effectors in colonic carcinogenesis.Colonic carcinogenesis is characterized by the accumulation of activating mutations in proto-oncogenes and inhibiting mutations in tumor suppressor genes. These mutations dysregulate pathways, including epidermal growth factor receptor (EGFR) signals that control cell growth, maturation, and cell death. Up-regulations of EGFRs and ligands have been described in many tumors, including colon cancers (1). Recently, we reported that EGFR signals were up-regulated in human aberrant crypt foci (ACF) identified in situ using image magnification chromoendoscopy (2). ACF are the earliest identifiable lesions in experimental colonic carcinogenesis and dysplastic ACF are believed to be precursors of colon cancer (3).EGFR (ErbB1) is a member of the ErbB family of receptor tyrosine kinases which also includes ErbB2, ErbB3, and ErbB4 (4). Ligand binding induces a conformational change, causing receptors to dimerize and activating the receptor's intrinsic tyrosine kinase. ErbB2 is unique in that it has no identified ligand, but is the preferred heterodimeric partner for other members. EGFR signals activate multiple pathways i...

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