EFFECTS OF FOLATE-DEFICIENT WESTERN-STYLE ON TRANSGENIC

Strang Cancer Prevention Center, New York NY

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Abstract

Decreased folic acid intake is one of the characteristics of a western diet. Folate acid deficiency is associated with DNA damage, impaired DNA repair and abnormal DNA methylation. Epidemiology suggests that dietary folic acid intake is inversely associated with colorectal cancer risk. Familial adenomatous polyposis (FAP) and hereditary non-polyposis colon cancer (HNPCC) are major contributors to colon cancer in man. Methylation has been proposed as a major modulator of certain HNPCC subtypes. This study focuses on the effects a folate-deficient western diet on genetically-altered transgenic mouse models for colorectal cancer in genetically at-risk humans . Specific objectives are to characterize and establish intermediate biomarkers for four transgenic models mouse models which imitate closely genetic alterations associated with colorectal cancer development in human. These shall include APC 1638 (FAP), MLH1 (HNPCC), and MLH1/APC1638 (HNPCC). Normal mice of the same strain are being used as controls. These studies include treatment of mice with both the western-style diet and the folate-deficient western style diet and the effects of these treatments on tumor development (including colorectal, small intestinal and other cancers), gross and microscopic pathology, cell proliferation, and apoptosis. The studies should demonstrate the efficacy of the test agents against colon cancer and additionally lead to the discovery and application of methylation pathways-specific chemopreventive agents.