High frequency of beta-catenin (ctnnb1) mutations in the colon tumors induced by two heterocyclic amines in the F344 rat.
Activating mutations in the beta-catenin (CTNNB1) gene corresponding to N-terminal phosphorylation sites in the protein have been implicated in the development of human colon cancer. To determine the possible involvement of such mutations during chemically induced colon carcinogenesis, we examined the corresponding region of Ctnnb1 in colon tumors induced in the F344 rat by two cooked meat heterocyclic amines, 2-amino-3-methylimidazo[4,5-f]quinoline and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). All of the colon tumors induced by 2-amino-3-methylimidazo[4,5-f]quinoline that were examined (5 of 5) and 4 of 7 PhIP-induced colon tumors had mutations within or flanking codons corresponding to important phosphorylation sites in beta-catenin. None of the colon tumors bearing Ctnnb1 mutations had genetic changes in the Apc gene, and those that contained wild-type Ctnnb1 were known from our previous work to contain Apc mutations. The results provide evidence for a major role of the beta-catenin/Apc pathway in the development of heterocyclic amine-induced colon tumors and give further weight to the view that regulation of beta-catenin is critical to the tumor suppressive effects of Apc during colon carcinogenesis. In contrast, Ctnnb1 mutations were completely absent in 23 PhIP-induced mammary tumors, in accordance with recent work showing that human breast carcinomas lack mutations in CTNNB1.
Dashwood
R H
RH
Division of Carcinogenesis, National Cancer Center Research Institute, Tokyo, Japan.
Suzui
M
M
Nakagama
H
H
Sugimura
T
T
Nagao
M
M
D000818:Animals; D003110:Colonic Neoplasms / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D007093:Imidazoles; D008325:Mammary Neoplasms, Experimental / Q000235:genetics; D009153:Mutagens; D009374:Neoplasms, Experimental / Q000235:genetics*; D017354:Point Mutation; D011804:Quinolines; D051381:Rats; D011916:Rats, Inbred F344; D015534:Trans-Activators; D051176:beta Catenin
C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D004273:DNA, Neoplasm; D007093:Imidazoles; D009153:Mutagens; D011804:Quinolines; D015534:Trans-Activators; D051176:beta Catenin; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine