Targeted Suppression of β-Catenin Blocks Intestinal Adenoma Formation in APC Min Mice
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Mutations involving the adenomatous polyposis coli (APC) tumor suppressor gene leading to activation of β-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-APCmin (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 β-catenin; molecular targeting of β-catenin is, thus, an attractive chemopreventative strategy in colon cancer. Antisense oligodeoxynucleotides (AODNs) capable of downregulating murine β-catenin have been identified.
Analysis of β-catenin Protein Expression in Liver Tissue and Intestinal Adenomas
Adenomas harvested from mice treated for 7 days with β-catenin AODNs demonstrated clear downregulation of β-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 β-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 β-catenin inhibits the formation of intestinal adenomas in APC-mutant mice. Furthermore, these studies suggest that molecular targeting of β-catenin holds significant promise as a chemopreventative strategy in colon cancer.
KeywordsBeta-catenin Adenoma Colon cancer Chemoprevention
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