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ß-Catenin Mutations and Protein Accumulation in All Hepatoblastomas Examined from B6C3F1 Mice Treated with Anthraquinone or Oxazepam

Laboratories of Molecular Carcinogenesis [C. H. A., T. R. D.] and Experimental Pathology [R. C. S., J. F. F., P. S. S., T-V. T.], National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709

The molecular pathogenesis of hepatoblastomas in the B6C3F1 mouse is unclear but may involve alterations in the ß-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 mutation frequency and spectrum of ß-catenin mutations and the intracellular localization of ß-catenin protein accumulation in chemically induced hepatoblastomas. In this study, ß-catenin mutations were identified in all 19 anthraquinone-induced hepatoblastomas and all 8 oxazepam-induced hepatoblastomas examined. Although several hepatoblastomas had multiple deletion and/or point mutations, the pattern of mutations in the hepatoblastomas did not differ from that identified in hepatocellular neoplasms. In a majority of the hepatoblastomas (six of seven) examined by immunohistochemical methods, both nuclear and cytoplasmic localization of ß-catenin protein were detected, whereas in hepatocellular adenomas, carcinomas, and normal liver only membrane staining was observed. Our data suggest that ß-catenin mutations and the subsequent translocation of ß-catenin protein from the cell membrane to the cytoplasm and nucleus may be critical steps in providing hepatocellular proliferative lesions with the growth advantage to progress to hepatoblastomas.

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