beta-Catenin mutations and protein accumulation in all hepatoblastomas examined from B6C3F1 mice treated with anthraquinone or oxazepam

The molecular pathogenesis of hepatoblastomas in the B6C3F1 mouse is unclea r but may involve alterations in the beta-catenin/Wnt signaling pathway as was recently described for chemically induced hepatocellular neoplasms and human liver cancers. The objective of this study was to characterize the mu tation frequency and spectrum of beta-catenin mutations and the intracellul ar localization of beta-catenin protein accumulation in chemically induced hepatoblastomas. In this study, beta-catenin mutations were identified in a ll 19 anthraquinone-induced hepatoblastomas and all 8 oxazepam induced hepa toblastomas examined. Although several hepatoblastomas had multiple deletio n and/or point mutations, the pattern of mutations in the hepatoblastomas d id not differ from that identified in hepatocellular neoplasms. In a majori ty of the hepatoblastomas (six of seven) examined by immunohistochemical me thods, both nuclear and cytoplasmic localization of beta-catenin protein we re detected, whereas in hepatocellular adenomas, carcinomas, and normal liv er only membrane staining was observed. Our data suggest that beta-catenin mutations and the subsequent translocation of beta-catenin protein from the cell membrane to the cytoplasm and nucleus may be critical steps in provid ing hepatocellular proliferative lesions with the growth advantage to progr ess to hepatoblastomas.