Mutational analysis of Ctnnb1 and Apc in tumors from rats given 1,2‐dimethylhydrazine or 2‐amino‐3‐methylimidazo[4,5‐f]quinoline: Mutational ‘hotspots’ and the relative expression of β‐catenin and c‐jun

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Abstract
There is growing interest in β‐catenin and its role in various human cancers. We recently reported that 2‐amino‐3‐methylimidazo[4,5‐f]quinoline (IQ)‐ and 1,2‐dimethylhydrazine (DMH)‐induced colon tumors in the rat contain mutations in Ctnnb1, the gene for β‐catenin, but the mutation spectrum was influenced by postinitiation exposure to chlorophyllin (CHL) and indole‐3‐carbinol (I3C) [Blum et al., Carcinogenesis 2001;22:315–320]. The present paper describes a follow‐up study in which all of the target organs for IQ‐ and DMH‐induced tumorigenesis were screened; Ctnnb1 mutations were found in 44 of 119 DMH‐induced colon tumors, six of 13 IQ‐induced colon tumors, 28 of 81 DMH‐induced small intestine tumors, none of five IQ‐induced small intestine tumors, four of 106 IQ‐induced liver tumors, none of 14 DMH‐induced Zymbal's gland tumors, none of 24 IQ‐induced Zymbal's gland tumors, and none of 29 IQ‐induced skin tumors. In tumors from rats given carcinogen alone, or carcinogen plus CHL or I3C, Ctnnb1 mutations frequently substituted amino acids adjacent to Ser33, a critical Ser/Thr residue in the glycogen synthase kinase‐3β regulatory domain of β‐catenin. However, substitution of critical Ser/Thr residues themselves was detected in only three of 24 (12.5%) of the tumors from rats given carcinogen alone, compared with 23 of 58 (40%) of the tumors from rats given carcinogen and treated postinitiation with I3C or CHL (P < 0.02). More than 50 of the colon tumors with wild‐type β‐catenin were examined further for their Apc status; the overall frequency of Apc mutations was Ctnnb1 mutations, but the expression was highest in tumors with Ctnnb1 mutations affecting Thr41 and Ser45 residues in the glycogen synthase kinase‐3β region of β‐catenin. Thus, Ctnnb1 mutations occurred more frequently than Apc mutations in colon and small intestine tumors of the rat, and certain mutations upregulated β‐catenin/T‐cell factor target genes more effectively than others, perhaps influencing the response to phytochemicals administered postinitiation.