Mechanism of Carcinogens - Genetic Alterations in Rodent and Human Tumors

Devereux, Theodora R.

Abstract

of Work: 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.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Environmental Health Sciences (NIEHS)
• Type: Intramural Research (Z01)
• Project #: 1Z01ES023006-07
• Application #: 6432267
• Study Section: (LMC)
• Support Year: 7
• Fiscal Year: 2000

Institution

• Name: U.S. National Inst of Environ Hlth Scis
• Country: United States

Publications

Anna, Colleen H; Iida, Mari; Sills, Robert C et al. (2003) Expression of potential beta-catenin targets, cyclin D1, c-Jun, c-Myc, E-cadherin, and EGFR in chemically induced hepatocellular neoplasms from B6C3F1 mice. Toxicol Appl Pharmacol 190:135-45

Iida, Mari; Anna, Colleen H; Hartis, Jennifer et al. (2003) Changes in global gene and protein expression during early mouse liver carcinogenesis induced by non-genotoxic model carcinogens oxazepam and Wyeth-14,643. Carcinogenesis 24:757-70

Tam, Andrew S; Devereux, Theodora R; Patel, Arti C et al. (2003) Perturbations of the Ink4a/Arf gene locus in aflatoxin B1-induced mouse lung tumors. Carcinogenesis 24:121-32

Devereux, Theodora R; Holliday, Wanda; Anna, Colleen et al. (2002) 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. Carcinogenesis 23:1737-43

Herzog, Christopher R; Devereux, Theodora R; Pittman, Brian et al. (2002) Carcinogenic induction directs the selection of allelic losses in mouse lung tumorigenesis. Cancer Res 62:6424-9

Zhang, Z; Wang, Y; Vikis, H G et al. (2001) Wildtype Kras2 can inhibit lung carcinogenesis in mice. Nat Genet 29:25-33

Devereux, T R; Stern, M C; Flake, G P et al. (2001) CTNNB1 mutations and beta-catenin protein accumulation in human hepatocellular carcinomas associated with high exposure to aflatoxin B1. Mol Carcinog 31:68-73

Mingchao; Devereux, T R; Stockton, P et al. (2001) Loss of E-cadherin expression in gastric intestinal metaplasia and later stage p53 altered expression in gastric carcinogenesis. Exp Toxicol Pathol 53:237-46

Sills, R C; Hong, H L; Boorman, G A et al. (2001) Point mutations of K-ras and H-ras genes in forestomach neoplasms from control B6C3F1 mice and following exposure to 1,3-butadiene, isoprene or chloroprene for up to 2-years. Chem Biol Interact 135-136:373-86

Hayashi, S; Hong, H H; Toyoda, K et al. (2001) High frequency of ras mutations in forestomach and lung tumors of B6C3F1 mice exposed to 1-amino-2,4-dibromoanthraquinone for 2 years. Toxicol Pathol 29:422-9