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.
Foley
Paul J
PJ
Department of Surgery, University of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, PA, 19104, USA.
Scheri
Randall P
RP
Smolock
Christopher J
CJ
Pippin
James
J
Green
Douglas W
DW
Drebin
Jeffrey A
JA
D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018390:Gene Targeting / Q000379:methods*; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental; D012334:RNA, Neoplasm / Q000235:genetics*; D016896:Treatment Outcome; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
C495267:CTNNB1 protein, mouse; D012334:RNA, Neoplasm; D051176:beta Catenin