Molecular Targets of Calcium and Vitamin D in Mouse Genetic Models of Intestinal Cancer

We have identified intracellular targets that are affected by vitamin D in intestinal epithelial cells in two ways: analyzing profiles of gene expression in a matrix of dietary-genetic interactions in mouse models, and exploring a novel mechanism of transcriptional attenuation. Genetic models of intestinal cancer in the mouse models included inheritance of a mutation in the Apc gene (Apc1638N /‐ mice 1,2 ) and the targeted inactivation in the mouse germ line of the Muc2 gene (Muc2 ‐/‐ mice 3 ) that encodes the major gastrointestinal mucin. Each of these models is highly significant in terms of the etiology and mechanism of human intestinal cancer. Inheritance of an Apc mutation, with its subsequent reduction to homozygosity due to somatic alteration of the remaining wild-type allele, is the etiology of familial adenomatous polyposis. Moreover, targeting of Apc somatically, or of the Wnt pathway in which it has an important role, is associated with almost all colorectal cancers. 4,5 Muc2 mutations have not yet been found in human colon tumors, but in the mouse Muc2 model, goblet cell differentiation is perturbed and the protective mucus layer in the small and large intestine is compromised. In this regard, goblet cells and the mucin they produce are often depleted in aberrant crypt foci (ACF), the earliest precursors to colon tumors. 6 Thus, the mucosa of the Muc2 ‐/‐ mouse may mimic focal changes that