Targeted suppression of beta-catenin blocks intestinal adenoma formation in APC Min mice.
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.
Duke Scholars
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- beta Catenin
- Treatment Outcome
- Surgery
- RNA, Neoplasm
- Neoplasms, Experimental
- Mice, Inbred C57BL
- Mice, Inbred BALB C
- Mice
- Immunohistochemistry
- Gene Targeting
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- beta Catenin
- Treatment Outcome
- Surgery
- RNA, Neoplasm
- Neoplasms, Experimental
- Mice, Inbred C57BL
- Mice, Inbred BALB C
- Mice
- Immunohistochemistry
- Gene Targeting