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.