beta-Catenin mutation in rat colon tumors initiated by 1,2-dimethylhydrazine and 2-amino-3-methylimidazo[4,5-f]quinoline, and the effect of post-initiation treatment with chlorophyllin and indole-3-carbinol. Carcinogenesis 2001 Feb;22(2):315-20
Date
02/22/2001Pubmed ID
11181454DOI
10.1093/carcin/22.2.315Scopus ID
2-s2.0-0035112690 (requires institutional sign-in at Scopus site) 61 CitationsAbstract
Carcinogens 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 1,2-dimethylhydrazine (DMH) induce colon tumors in the rat that contain mutations in beta-catenin, but the pattern of mutation differs from that found in human colon cancers. In both species, mutations affect the glycogen synthase kinase-3beta consensus region of beta-catenin, but whereas they directly substitute critical Ser/Thr phosphorylation sites in human colon cancers, the majority of mutations cluster around Ser33 in the rat tumors. Two dietary phytochemicals, chlorophyllin and indole-3-carbinol, given post-initiation, shifted the pattern of beta-catenin mutations in rat colon tumors induced by IQ and DMH. Specifically, 17/39 (44%) of the beta-catenin mutations in groups given carcinogen plus modulator were in codons 37, 41 and 45, and substituted critical Ser/Thr residues directly, as seen in human colon cancers. None of the tumors from groups given carcinogen alone had mutations in these codons. Interestingly, many of the mutations that substituted critical Ser/Thr residues in beta-catenin were from a single group given DMH and 0.001% chlorophyllin, in which a statistically significant increase in colon tumor multiplicity was observed compared with the group given DMH only. These tumors had marked over-expression of cyclin D1, c-myc and c-jun mRNA and c-Myc and c-Jun proteins were strongly elevated compared with tumors containing wild-type beta-catenin. The results indicate that the pattern of beta-catenin mutations in rat colon tumors can be influenced by exposure to dietary phytochemicals administered post-initiation, and that the mechanism might involve the altered expression of beta-catenin/Tcf/Lef target genes.
Author List
Blum CA, Xu M, Orner GA, Fong AT, Bailey GS, Stoner GD, Horio DT, Dashwood RHMESH terms used to index this publication - Major topics in bold
1,2-DimethylhydrazineAnimals
Anticarcinogenic Agents
Carcinogens
Chlorophyllides
Colonic Neoplasms
Cyclin D1
Cytoskeletal Proteins
DNA Mutational Analysis
Hypoxanthine Phosphoribosyltransferase
Indoles
Male
Mutation
Polymorphism, Single-Stranded Conformational
Proto-Oncogene Proteins c-jun
Proto-Oncogene Proteins c-myc
Quinolines
Rats
Rats, Inbred F344
Reverse Transcriptase Polymerase Chain Reaction
Trans-Activators
beta Catenin