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.
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.
Blum
C A
CA
Linus Pauling Institute and Department of Environment and Molecular Toxicology, Oregon State University, Corvallis, OR 97331-6512, USA.
Xu
M
M
Orner
G A
GA
Fong
A T
AT
Bailey
G S
GS
Stoner
G D
GD
Horio
D T
DT
Dashwood
R H
RH
D019813:1,2-Dimethylhydrazine / Q000008:administration & dosage; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D002273:Carcinogens / Q000008:administration & dosage*; D002735:Chlorophyllides / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism; D007211:Indoles / Q000627:therapeutic use; D008297:Male; D009154:Mutation; D018807:Polymorphism, Single-Stranded Conformational; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D011804:Quinolines / Q000008:administration & dosage; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators; D051176:beta Catenin
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D002735:Chlorophyllides; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D007211:Indoles; D016755:Proto-Oncogene Proteins c-jun; D016271:Proto-Oncogene Proteins c-myc; D011804:Quinolines; D015534:Trans-Activators; D051176:beta Catenin; D019938:Cyclin D1; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; C016517:indole-3-carbinol; D007041:Hypoxanthine Phosphoribosyltransferase; C007020:chlorophyllin; D019813:1,2-Dimethylhydrazine