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Targeted Inactivation of p27^kip1 Is Sufficient for Large and Small Intestinal Tumorigenesis in the Mouse, Which Can Be Augmented by a Western-Style High-Risk Diet¹

Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, New York 10467

Mice with a targeted inactivation of both alleles of the cyclin-dependent kinase inhibitor p27^kip1 developed both small and large intestinal adenomas when fed a control AIN-76A diet. A Western-style diet that is high in fat and phosphate and low in calcium and vitamin D was also able to initiate adenoma formation in wild-type mice. The combination of p27^kip1 inactivation and the Western-style diet was additive in terms of tumor incidence, frequency and size, and in reducing the life span of the mice. The genetic and dietary combination also resulted in development of adenocarcinoma. Tumor formation was linked to a disruption in homeostasis of the intestinal mucosa, involving increased cell proliferation and decreased apoptosis. There was also decreased goblet cell differentiation as assessed by alcian blue staining and expression of the Muc2 gene, especially in mice fed the Western-style diet, although this differentiation lineage was still present as indicated by expression and staining for intestinal trefoil factor. The inactivation of p27^kip1 and the consequent disruption of normal colonic cell maturation in the mucosa were associated with modestly elevated c-myc, cdk4, and cyclin D1 expression. These data establish a fundamental role for p27^kip1 in maintenance of intestinal cell homeostasis and in suppressing tumor formation. The data also emphasize the critical role that dietary factors can have in both tumor initiation and progression through interaction with pathways that normally maintain intestinal homeostasis.

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