Different mutation status of the β‐catenin gene in carcinogen‐induced colon, brain, and oral tumors in rats

Abstract

Mutations in the region corresponding to the N-terminal phosphorylation sites (codons 1-51) of the rat beta-catenin gene (Ctnnb1) were investigated in rat colon tumors induced by 1-hydroxyanthraquinone (1-HA) plus methylazoxymethanol (MAM) acetate, by using polymerase chain reaction (PCR)-single-strand conformation polymorphism (SSCP) analysis. The beta-catenin gene was also screened for mutations in rat brain and oral tumors induced by ethyl nitrosourea (ENU) and 4-nitroquinoline 1-oxide (4-NQO), respectively. In colon tumors, beta-catenin gene mutations were found in two of three adenomas (67%) and 26 of 28 adenocarcinomas (93%), with a total incidence of 90% (28 of 31 adenomas plus adenocarcinomas). Eight (29%) were (34)G-->T (second position), eight (29%) were (32)G-->A (first position), five (18%) were (34)G-->A (first position), five (18%) were (41)C-->T (second position), one (4%) was (34)G-->A (second position), and one (4%) was (32)A-->G (second position), mutations, resulting in the substitutions of Gly(34)-->Val, Asp(32)-->Asn, Gly(34)-->Arg, Thr(41)-->Ile, Gly(34)-->Glu, and Asp(32)-->Gly, respectively. The (34)G-->T (second position) mutations found in this study were unique compared to those found in other carcinogen-induced rat colon carcinogenesis models. In contrast, beta-catenin gene mutations were not found in either the brain or oral tumors. These results suggest that mutations in the beta-catenin gene in rat tumors occur in specific tissues or organ sites and in a carcinogen-specific manner. Thus, the mutation spectrum in the beta-catenin gene is organ- and chemical carcinogen-specific.

The Cycad Genotoxin MAM Modulates Brain Cellular Pathways Involved in Neurodegenerative Disease and Cancer in a DNA Damage-Linked Manner

“…Our data support the hypothesis that MAM-induced O 6 -mG DNA lesions alter purine metabolism and modulate cell-signaling pathways associated with both neurodegeneration and cancer. While MAM does not induce brain tumors in singly treated adult mice, the genotoxin consistently triggers tumors in peripheral organs, notably the intestine [37], [38]. The prominent modulation of “cancer genes” in the “tumor-insensitive” brains of MAM-treated adult animals suggests that perturbations of these genes in the brain have consequences other than cancer.…”

Preneoplasia and carcinogenesis of the oral cavity

“…Although molecular alterations are infrequent in 4-NQOinduced rat tongue carcinomas [59,60], our recent study has revealed that 4-NQO treatment for eight weeks could more rapidly induce (within eight weeks) tongue dysplasia, squamous cell papillomas and squamous cell carcinoama in male and female transgenic rats carrying the human c-Ha-ras proto-oncogene [61], when compared to wild rats, suggesting that alterations of c-Ha-ras are involved in 4-NQO- induced tongue carcinogenesis, especially the early phase of carcinogenesis. Interestingly, this transgenic rat also develops taste bud tumors [62,63].…”

β‐Catenin mutations and nuclear accumulation during progression of rat stomach adenocarcinomas

“…29,30) Mutations were found in codons 33, 37, 41, and 45, encoding serine and threonine that are direct targets for phosphorylation by GSK-3β. Also reported were alterations of codons 32, 34, and 35, neighboring serine and threonine residues, possibly resulting in conformational changes and abnormal phosphorylation of the β-catenin protein.…”