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Nutrition and Disease

Dietary Calcium and Cholecalciferol Modulate Cyclin D1 Expression, Apoptosis, and Tumorigenesis in Intestine of adenomatous polyposis coli^1638N/+ Mice^1,2

³ Strang Cancer Research Laboratory, Department of Medicine (Gastroenterology and Hepatology), Weill Medical College of Cornell University, New York, NY 10065; ⁴ Albert Einstein College of Medicine, Bronx, NY 10461; ⁵ Department of Chemical Biology, Rutgers University, Piscataway, NJ 08854; ⁶ Division of Cancer Prevention, National Cancer Institute, NIH, Bethesda, MD 20892; and ⁷ Harvard Partners Center for Genetics and Genomics, Boston, MA 02115

Both epidemiological and experimental findings have indicated that components of Western diets influence colonic tumorigenesis. Among dietary constituents, calcium and cholecalciferol have emerged as promising chemopreventive agents. We have demonstrated that a Western-style diet (WD) with low levels of calcium and cholecalciferol and high levels of (n-6) PUFA, increased the incidence of neoplasia in mouse intestine compared with a standard AIN-76A diet; models included wild-type mice and mice with targeted mutations. In the present study, adenomatous polyposis coli (Apc)^1638N/+ mice carrying a heterozygous Apc mutation were fed either an AIN-76A diet, a WD, or a WD supplemented with calcium and cholecalciferol (WD/Ca/VitD3). Diets were fed for 24 wk and effects on cellular and molecular events were assessed by performing immunohistochemistry in colonic epithelium along the crypt-to-surface continuum. Feeding WD to Apc^1638N/+ mice not only enhanced cyclin D1 expression in colonic epithelium compared with AIN-76A treatment as previously reported but also significantly increased the expression of the antiapoptotic protein B-cell lymphoma 2 (Bcl-2) concomitantly with a decrease in the proapoptotic Bcl2-associated X protein and the number of apoptotic epithelial cells. WD treatment enhanced mutant Apc-driven small intestinal carcinogenesis and also resulted in the formation of a small number of colonic adenomas (0.16 ± 0.09; P < 0.05). By contrast, the WD/Ca/VitD3 diet reversed WD-induced growth, promoting changes in colonic epithelium. Importantly, Apc^1638N/+ mice fed the WD/Ca/VitD3 diet did not develop colonic tumors, further indicating that dietary calcium and cholecalciferol have a key role in the chemoprevention of colorectal neoplasia in this mouse model of human colon cancer.

^* To whom correspondence should be addressed. E-mail: lipkin{at}mail.rockefeller.edu.

Manuscript received 11 February 2008. Initial review completed 31 March 2008. Revision accepted 26 June 2008.

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