TY - JOUR
T1 - Mutational analysis of Ctnnb1 and Apc in tumors from rats given 1,2-dimethylhydrazine or 2-amino-3-methylimidazo[4,5-f]quinoline
T2 - Mutational 'hotspots' and the relative expression of β-catenin and c-jun
AU - Blum, Carmen A.
AU - Tanaka, Tomoko
AU - Zhong, Xiaoying
AU - Li, Qingjie
AU - Dashwood, Wan Mohaiza
AU - Pereira, Clifford
AU - Xu, Meirong
AU - Dashwood, Roderick H.
PY - 2003/4/1
Y1 - 2003/4/1
N2 - 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 <10%, and these genetic changes occurred exclusively in the 'Mutation Cluster Region' of Apc. A subset of colon tumors also was examined for expression of β-catenin and c-jun; these proteins were overexpressed in all tumors containing 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.
AB - 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 <10%, and these genetic changes occurred exclusively in the 'Mutation Cluster Region' of Apc. A subset of colon tumors also was examined for expression of β-catenin and c-jun; these proteins were overexpressed in all tumors containing 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.
KW - APC
KW - CTNNB1
KW - Chlorophyllin
KW - Indole-3-carbinol
KW - TCF/LEF target genes
KW - Wnt signaling
UR - http://www.scopus.com/inward/record.url?scp=0037389837&partnerID=8YFLogxK
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U2 - 10.1002/mc.10112
DO - 10.1002/mc.10112
M3 - Article
C2 - 12669311
AN - SCOPUS:0037389837
SN - 0899-1987
VL - 36
SP - 195
EP - 203
JO - Molecular Carcinogenesis
JF - Molecular Carcinogenesis
IS - 4
ER -