Epidermal growth factor receptor is required for colonic tumor promotion by dietary fat in the azoxymethane/dextran sulfate sodium model: roles of transforming growth factor-{alpha} and PTGS2.

ABSTRACT

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 x C57BL6/J mice with wild-type Egfr (Egfr(wt)) or loss-of-function 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 real-time 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-alpha, 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-alpha 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.