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These studies identify critical target genes and alterations in genes that may be important in chemical carcinogenesis. Genetic alterations in oncogenes (eg.-ras, beta-catenin) and tumor suppressor genes (eg. - p53 and p16) from rodent tumors induced by certain carcinogens and from human cancers of individuals exposed to environmental agents are being characterized in order to understand mechanisms of chemical carcinogenesis.
In one set of investigations beta-catenin mutations have been identified in chemically induced mouse liver tumors. Antraquinone and oxazepam caused significant increases in mouse hepatoblastomas, a more malignant form of hepatocellular carcinoma and a rare tumor in untreated mice. Beta-catenin mutations were identified in all these tumors examined, and beta-catenin protein accumulated in the cytoplasm and nucleus of the hepatocytes. These results are different from those in hepatocellular neoplasms in which the beta-catenin accumulated only along the cell membranes in those tumors with mutations. A low frequency of beta-catenin mutations were identified in human hepatocellular carcinomas associated with high exposure to aflatoxin B1. Identification of other proteins that interact with beta-catenin in liver is now being studied. We are now studying gene expression profiles by microarray analysis in liver after chronic treatment of mice with certain classes of "non-genotoxic" carcinogens to identify expression biomarkers that can be used to identify other carcinogens. Markers of oxidative stress are also being analyzed in these liver samples. We are also continuing our study to identify mouse lung tumor susceptibility genes that may have relevant human homologs, and we are concentrating on the Par2 locus on chromosome 18.