Frequent mutations of the rat beta-catenin gene in colon cancers induced by methylazoxymethanol acetate plus 1-hydroxyanthraquinone

Recent evidence suggests that the beta-catenin gene (CTNNB1) acts as an onc ogene, and some human colon tumors with an intact APC gene have activating mutations in CTNNB1. In this study, mutations in the region corresponding t o N-terminal phosphorylation sites (codons 1-51) of the rat Ctnnb1 gene wer e investigated in 20 colon tumors associated with ulcerative colitis and in duced with methylazoxymethanol acetate and 1-hydroxyanthraquinone. Ninety p ercent (18 of 20) of the tumors induced in male F344 rats harbored mutation s, which were detected in three of four adenomas (75%) and 15 of 16 adenoca rcinomas (94%). Of 18 total missense mutations, 13 (72%) were G-->A transit ions at position 101, three were G-->A transitions at position 94, and two were C-->T transitions at position 122, resulting in the amino acid substit utions Gly(34)-->Glu, Asp(32)-->Asn, and Thr(41)-->Ile, respectively. Altho ugh there were no mutations in the Apc gene, as we previously reported in t he same tumor samples, the results obtained in this study strongly implicat e the Apc-beta-catenin-T-cell factor (Tcf) signaling pathway in methylazoxy methanol acetate, 1-hydroxyanthraquinone-induced colon carcinogenesis. Mel. Carcinog. 24:232-237, 1999. (C) 1999 Wiley-Liss, Inc.