Role of c-Myc in intestinal tumorigenesis of the Apc^Min/+ mouse

The c-MYC oncogene plays an important role in tumorigenesis and is commonly highly expressed in gastrointestinal cancers. In colon cells, c-MYC is regulated by the adenomatous polyposis coli (Apc) tumor suppressor gene. Multiple intestinal neoplasia (Apc^Min/+ or Min) mice are heterozygous for a truncating Apc mutation and serve as a model of familial adenomatous polyposis (FAP) disease. To study the role of c-Myc in the mutant Apc-mediated colon tumorigenesis, we have developed a transgenic mouse with the conditional deletion of the floxed c-Myc alleles in the intestinal crypts of Apc ^Min/+ mice (Apc^Min/+; c-Myc^fl/fl). The floxed c-Myc deletion was initiated via a Cre recombinase controlled by the intestine-specific transcriptional regulatory elements of the liver fatty acid-binding protein gene (Fabpl^4xat-132). Fabpl^4xat-132- mediated Cre expression and recombination resulted in a two-fold decrease in c-MYC protein expression with no effect on intestinal tract morphology. Small intestinal tumorigenesis was significantly suppressed throughout the small intestinal tract of Apc^Min/+; c-Myc^fl/fl mice compared to c-Myc wild type littermates. In Apc^Min/+; c-Myc^fl/fl mice, the intestinal apoptosis was higher in the areas of the small intestine with the decreased c-Myc protein expression (p = 0.0016, compared to their littermates with the wild type c-Myc). Thus, conditional inactivation of c-Myc, mediated by Fabpl^4xat-132-driven Cre-recombinase, suppresses Apc-dependent intestinal tumorigenesis in adult Apc^Min/+ mice, without apparent effect on normal intestinal mucosa.