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J Gastrointest Surg. 2008 Aug;12(8):1452-8. doi: 10.1007/s11605-008-0519-6. Epub 2008 Jun 3.

Targeted suppression of beta-catenin blocks intestinal adenoma formation in APC Min mice.

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Department of Surgery, University of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, PA, 19104, USA.



Mutations involving the adenomatous polyposis coli (APC) tumor suppressor gene leading to activation of beta-catenin have been identified in the majority of sporadic colonic adenocarcinomas and in essentially all colonic tumors from patients with Familial Adenomatous Polyposis. The C57BL/6J-APC(min) (Min) mouse, which carries a germ line mutation in the murine homolog of the APC gene is a useful model for intestinal adenoma formation linked to loss of APC activity. One of the critical downstream molecules regulated by APC is beta-catenin; molecular targeting of beta-catenin is, thus, an attractive chemopreventative strategy in colon cancer. Antisense oligodeoxynucleotides (AODNs) capable of downregulating murine beta-catenin have been identified. ANALYSIS OF beta-CATENIN PROTEIN EXPRESSION IN LIVER TISSUE AND INTESTINAL ADENOMAS: Adenomas harvested from mice treated for 7 days with beta-catenin AODNs demonstrated clear downregulation of beta-catenin expression, which was accompanied by a significant reduction in proliferation. There was no effect on proliferation in normal intestinal epithelium. Min mice treated systemically with beta-catenin AODNs over a 6-week period had a statistically significant reduction in the number of intestinal adenomas. These studies provide direct evidence that targeted suppression of beta-catenin inhibits the formation of intestinal adenomas in APC-mutant mice. Furthermore, these studies suggest that molecular targeting of beta-catenin holds significant promise as a chemopreventative strategy in colon cancer.

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