Western Diet-Fed Mice With Inherited Cancer Predisposition Reveal Early Epigenetic Changes And Protein Markers For Colon Oncogenesis

Colorectal cancer (CRC) is the second most common cause of cancer-related deaths in the Western world. Interactions between genetic and environmental factors, such as diet, are suggested to play a critical role in its etiology. However, the mechanisms that mediate the effects of diet on oncogenesis are largely unknown. We conducted a long-term feeding experiment in the mouse to address epigenetic changes arising in normal colonic mucosa and their functional consequences as putative cancer-predisposing events available for early detection. The quantitative analysis of proteomes and the expression of 94 growth-regulatory genes previously linked to human CRC and aberrant hypermethylation were studied at two time points (5 weeks and 12 months of age) in the heterozygote Mlh1+/- mice analogous to human Lynch syndrome, and wild type Mlh1+/+ littermates, fed with Western-style (WD) or AIN-93G control diet. In the proteome study the most significant expression changes were found in the Mlh1+/- WD mice compared to mice fed with AIN-93G control diet and the 19 identified proteins mainly point to abnormities in energy metabolism and protein unfolding. We further found that in mice carrying Mlh1 mutation and/or fed with WD, histologically normal proximal colonic mucosa exhibited a significant expression decrease in tumor suppressor genes, Dkk1, Slc5a8, Hoxd1, and Socs1. Especially in Dkk1, a secreted antagonist of the Wnt/β-catenin pathway the reduced expression was associated with its promoter hypermethylation. The fact that changes in Dkk1 seem to predispose to neoplasia in the proximal colon and that 5 out of 6 mice with neoplastic colonic lesions were fed with WD suggests that the found expression changes are early markers for oncogenesis. Citation Format: Denis Dermadi Bebek, Satu Valo, Marjaana Pussila, Nima Reyhani, Laura Sarantaus, Minna Nystrom. Western diet-fed mice with inherited cancer predisposition reveal early epigenetic changes and protein markers for colon oncogenesis. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr B18.