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

• Published in: Cancer science 2003-12, Vol.94 (12), p.1046-1051
• Main Authors: Tsukamoto, Tetsuya, Yamamoto, Masami, Ogasawara, Naotaka, Ushijima, Toshikazu, Nomoto, Tomoko, Fujita, Hirofumi, Matsushima, Taijiro, Nozaki, Koji, Cao, Xueyuan, Tatematsu, Masae
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Adenocarcinoma - chemically induced; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Animal models; Animals; Base Sequence; beta Catenin - genetics; Biological and medical sciences; Carcinogenesis; Carcinogens - toxicity; Catenin; Cell membranes; Cell Nucleus - metabolism; Cytology; Disease Progression; Drinking water; Gastric cancer; Glycine; Immunohistochemistry; Localization; Male; Medical sciences; Methylnitronitrosoguanidine - toxicity; Morphology; Mucosa; Mutation; Phosphorylation; Polarity; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Rats; Rodents; Serine; Stomach; Stomach Neoplasms - chemically induced; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; Threonine; Tumors; Wnt protein
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/j.1349-7006.2003.tb01399.x

Aberrant Wnt/β‐catenin signaling caused by mutations in exon 3 of the β‐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 β‐catenin localization. Fourteen tumors (63.6%) that showed homogeneous low‐grade morphology, preserving cell polarity, were found to harbor β‐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 β‐catenin in small regions. The remaining 4 tumors (18.2%) contained more dysplastic regions that displayed nuclear (N) β‐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 β‐catenin. In contrast all of 3 regions with N staining featured mutations (3 of 3=100%; N vs. C, P