Our recent studies identified 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. We have found that beta-catenin gene mutation and protein accumulation occur commonly in some chemically induced mouse liver tumors. Now we have identified other proteins that interact with beta-catenin in liver tumors. Cyclin D1, a target for beta-catenin/Wnt signaling, is strongly upregulated in hepatoblastomas and to a lesser extent in hepatocellular tumors. Increased cyclin D1 expression correlated strongly with beta-catenin mutations, while c-Jun increased expression did not. We are now utilizing global gene expression profiling and proteomics methods to investigate changes that play a role in the development of chemically induced mouse liver and lung tumors. For the mouse liver carcinogenesis model we have used treatments with oxazepam or Wyeth-14,643 and examined livers at 2 weeks up to 6 months in an age matched control bioassay, in which the livers do not exhibit foci or neoplasia by 6 months. For the mouse lung carcinogenesis model we are studying lung tumors induced by various chemicals and lung cell lines from different strains of inbred mice. We have found that map kinase activation correlates with K-ras mutation and loss of heterozygosity on chromosome 6 in alveolar bronchiolar carcinomas from B6C3F1 mice exposed to vanadium pentoxide for 2 years. These experiments provided more evidence that wild type K-ras may be a tumor suppressor gene in mouse lung. We are also continuing our study to identify the Par2 mouse lung tumor susceptibility gene on chromosome 18 that may have a relevant human homolog. Due to the near completion of the human and mouse genome projects, we have narrowed the locus to a small region. We are sequencing regions to identify single nucleotide polymorphisms that can be used for fine mapping the region with congenic mice and are identifying candidate genes in the region.
Showing the most recent 10 out of 20 publications
