Mechanism of Carcinogens - Genetic Alterations in Rodent and Human Tumors

Devereux, T 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) 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 H-ras and K-ras mutation frequencies and profiles are being compared in lung and harderian tumors from B6C3F1 mice exposed to isoprene, chloroprene and butadiene in order to study mechanisms of carcinogenesis of these structurally related compounds. In another study comparative genomic hybridization (CGH) is being used to screen mouse lung tumors induced by methylene chloride for genetic losses or gains. The mechanism of methylene chloride carcinogenesis is still unclear, and our findings may indicate regions of oncogene or tumor suppressor gene involvment. A set of human bladder tumors from a cohort of people occupationally exposed to benzidine is also being examined by CGH for gains or losses of genetic material. We are also continuing our study to identify murine lung tumor susceptibility genes that may have relevant human homologs. In collaboration with Drs. Ming You and Michael Festing we identified a locus (designated Par2) on distal chromosome 18 that may represent an important tumor resistance gene in BALB/c mice. This gene maps to the region of synteny with human chr. 18q21.1 that harbors the DCC, DPC4 and JV18-1 genes that are putative tumor suppressor genes. We have now completed a study that examined the mouse homologs of DPC4 and JV18-1 (Smad4 and Smad2) as candidate genes for the Par2 mouse lung tumor resistance gene. We found no evidence to indicate that either Smad4 or Smad2 is involved in mouse lung tumorigenesis or is a good candidate for the Par2 lung tumor resistance locus on distal chr. 18.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Environmental Health Sciences (NIEHS)
• Type: Intramural Research (Z01)
• Project #: 1Z01ES023006-04
• Application #: 6162151
• Study Section: Special Emphasis Panel (LMC)
• Support Year: 4
• Fiscal Year: 1997

Institution

• Name: National Institute of Environmental Health Sciences
• 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

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

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