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AKR/J mice are resistant to the tumorigenic properties of the colon carcinogen, azoxymethane (AOM). Upon AOM exposure, only limited numbers of preneoplastic lesions, referred to as aberrant crypt foci (ACF), are formed in the colon, and tumor progression is a rare event. To determine whether inherent tumor resistance can be overcome by concomitant exposure to a dietary tumor promoter, AOM-exposed AKR/J mice were fed a diet containing 0.25% deoxycholic acid (DCA). DCA exposure was begun one week prior to or one week after initiation with AOM. Mice started on the DCA diet prior to AOM developed a higher number of ACF (2-fold) compared to AOM exposed non-DCA fed mice (15.5 ± 0.96 vs. 6.17 ± 0.48 respectively). However, when DCA exposure was started after AOM treatment (post-initiation), ACF formation was further enhanced (up to 4-fold) and colonic lesions were characterized by a higher degree of dysplasia (34.00 ± 1.22). The increase in ACF number was correlated with the presence of nuclear β-catenin, assessed by immunohistochemical staining. In fact, 77% of ACF in the colons of mice fed DCA after AOM had positive β-catenin nuclear staining. In contrast, only 33% of ACF from mice exposed to DCA prior to AOM treatment contained positive staining nuclei. These results indicate that exposure to DCA, an important digestive component, is sufficient to sensitize a resistant colonic epithelium to formation of high-grade dysplasia, and further suggest that β-catenin nuclear translocation may play a key role in DCA-mediated colonic dysplasia.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]