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[Cancer Research 61, 565-569, January 15, 2001]
© 2001 American Association for Cancer Research

Tumor Biology

Targeted Inactivation of the p21WAF1/cip1 Gene Enhances Apc-initiated Tumor Formation and the Tumor-promoting Activity of a Western-Style High-Risk Diet by Altering Cell Maturation in the Intestinal Mucosa1

Wan Cai Yang, Joseph Mathew, Anna Velcich, Winfried Edelmann, Raju Kucherlapati, Martin Lipkin, Kan Yang and Leonard H. Augenlicht2

Albert Einstein Cancer Center, Bronx, 10467 [W. C. Y., J. M., A. V., W. E., R. K., L. H. A.], and Strang Cancer Prevention Center, New York, New York 10021 [M. L., K. Y.]

Elimination of both alleles of the gene that encodes the cyclin kinase inhibitor p21WAF1/cip1 increases the frequency and size of intestinal tumors in Apc1638+/- mice that inherit a mutant allele of the Apc gene, and intermediate effects are seen if a single p21 allele is inactivated. The increased tumor formation is associated with altered cell maturation in the intestinal mucosa of the p21-deficient mice—increased cell proliferation, and decreased apoptosis, and goblet cell differentiation—that is also a function of p21 gene dosage. Moreover, a Western-style diet that mimics principal risk factors for colon cancer (high fat and phosphate, low calcium and vitamin D) accelerates tumor formation in Apc1638+/- mice, and the loss of a single or both p21 alleles is additive with the tumor-promoting effects of this diet, resulting in more and larger tumors, and a highly significant decrease in survival time. Thus, p21 normally suppresses Apc-initiated tumor formation and is haplo-insufficient in this regard. This is consistent with recent reports that Apc initiates tumor formation by up-regulating c-myc expression through altered ß-catenin-Tcf signaling and that c-myc then up-regulates cdk4, whose activity is inhibited by p21. Decreased expression of p21 is also a marker of poor prognosis in patients, and the data presented suggest that dietary alterations in patients undergoing treatment for colon cancer might be highly effective in improving outcome.




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