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No Effects of Smad2 (Madh2) Null Mutation on Malignant Progression of Intestinal Polyps in Apc⁷¹⁶ Knockout Mice¹

Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan [K. T., M. M. T.]; Laboratory of Biomedical Genetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan [K. T., M. M. T.]; Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada [J. L. W.]; and Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138 [E. J. R.]

The loss of heterozygosity (LOH) in human chromosome 18q21 is found at high frequencies in advanced pancreatic and colorectal cancers. Several candidate tumor suppressor genes, such as SMAD2, SMAD4, and DCC, are located in this region. The homologues of these genes in the mouse are also clustered on chromosome 18. Mutations in the adenomatous polyposis coli (APC) gene are responsible for familial adenomatous polyposis, and we earlier constructed a mouse model for familial adenomatous polyposis, Apc⁷¹⁶. Although human APC is located on chromosome 5q, mouse Apc is on chromosome 18, 30 cM proximal to the Dcc-Smad4-Smad2 locus. Taking advantage of this fact, we constructed previously a cis-compound Apc⁷¹⁶ Smad4 mutant, the intestinal polyps of which progress to very invasive adenocarcinomas. To determine whether Smad2 mutations play similar roles in malignant progression, here we constructed compound mutant mice carrying Apc and Smad2 knockouts in the cis configuration. In contrast to the cis-compound Apc⁷¹⁶ Smad4 heterozygotes, the polyps in the cis-compound Apc⁷¹⁶ Smad2 heterozygotes showed no difference in the number, size, or histopathology from the polyps in the simple Apc⁷¹⁶ heterozygotes. These results suggest that, on human chromosome 18q21, the SMAD4 LOH plays a more significant role, and SMAD2 LOH is insufficient to cause malignant progression of colonic polyps.

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