title: beta-Catenin mutations and nuclear accumulation during progression of rat stomach adenocarcinomas.
abstract: Aberrant Wnt/beta-catenin signaling caused by mutations in exon 3 of the beta-catenin gene has been identified in a number of human malignancies, including stomach cancer. However, studies of mutation frequency have yielded conflicting results, and timing during progression remains largely unknown. In this study, we utilized an animal model to address this question. A total of 20 ACI male rats were treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in the drinking water and 22 induced differentiated adenocarcinomas were histopathologically and immunohistochemically evaluated for beta-catenin localization. Fourteen tumors (63.6%) that showed homogeneous low-grade morphology, preserving cell polarity, were found to harbor beta-catenin protein on the cell membranes (M). Eight tumors exhibited regions of high-grade morphology among areas with low-grade morphology, and they were characterized by denser cell growth and loss of cell polarity. Among these 8 tumors, 4 (18.2%) showed cytoplasmic localization (C) of beta-catenin in small regions. The remaining 4 tumors (18.2%) contained more dysplastic regions that displayed nuclear (N) beta-catenin staining. Analysis of DNA obtained by microdissection demonstrated that all of 4 regions with C staining and 20 with M staining, as well as 17 samples of surrounding normal mucosa (S) had wild-type beta-catenin. In contrast, all of 3 regions with N staining featured mutations (3 of 3 = 100%; N vs. C, P < 0.05; N vs. M and N vs. S, P < 0.001, Fisher's exact test) in exon 3, at glycine 34, threonine 41, and serine 45, which affected phosphorylation sites. In conclusion, beta-catenin mutations appear to be associated with the late progression stage of adenocarcinoma development in rat stomach carcinogenesis, in contrast to the case of colorectal cancers, in which mutations appear to occur in the early stages.
authors.affiliation: Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681. ttsukamt@aichi-cc.jp
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tsukamoto
authors.forename: Masami
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Naotaka
authors.initials: N
authors.lastname: Ogasawara
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Ushijima
authors.forename: Tomoko
authors.initials: T
authors.lastname: Nomoto
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Fujita
authors.forename: Taijiro
authors.initials: T
authors.lastname: Matsushima
authors.forename: Koji
authors.initials: K
authors.lastname: Nozaki
authors.forename: Xueyuan
authors.initials: X
authors.lastname: Cao
authors.forename: Masae
authors.initials: M
authors.lastname: Tatematsu
mesh_terms: D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D001483:Base Sequence; D002273:Carcinogens / Q000633:toxicity; D002467:Cell Nucleus / Q000378:metabolism; D018450:Disease Progression; D007150:Immunohistochemistry; D008297:Male; D008769:Methylnitronitrosoguanidine / Q000633:toxicity; D009154:Mutation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D051381:Rats; D013274:Stomach Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology*; D051176:beta Catenin / Q000235:genetics*
chemical_list: D002273:Carcinogens; D051176:beta Catenin; D008769:Methylnitronitrosoguanidine