Alterations at the Ink4a locus in transplacentally induced murine lung tumors.
The malignant phenotype results from multiple genetic alterations, including the activation of oncogenes and inactivation of tumor suppressor genes. Activation of the Ki-ras oncogene has been implicated as an early event in the pathogenesis of lung adenocarcinomas in humans and experimental animal models. Previous studies from this laboratory have shown that, following treatment of pregnant [D2 x B6D2F(1)]F(2) or Balb/c mice with the polycyclic aromatic hydrocarbon, 3-methylcholanthrene (MC), lung tumors from the transplacentally exposed offspring exhibited a high incidence of mutations in the Ki-ras gene. The role of genetic alterations at other oncogenic or tumor suppressor loci that can mediate lung tumor initiation and/or progression have not been well characterized in either human or murine models. Using the transplacental carcinogenesis model, which results in the induction of both lung and liver tumors following in utero exposure to MC, the results of this and our previous studies show that alterations in the Ink4a locus occur in only 15 and 27% of the lung and liver tumors, respectively. Preliminary data also suggests that the type of mutation induced in the Ki-ras gene following the initial exposure to MC may influence lung tumor progression. These results imply that damage to the Ink4a gene is not a frequent pathway to malignant progression in mouse lung and liver tumors following in utero exposure to environmental carcinogens.
Mizesko
M C
MC
Department of Cancer Biology, Comprehensive Cancer Center, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1082, USA.
Grewe
C
C
Grabner
A
A
Miller
M S
MS
D000818:Animals; D001483:Base Sequence; D002273:Carcinogens; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D019175:DNA Methylation; D011905:Genes, ras / Q000235:genetics; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics*; D008748:Methylcholanthrene; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D011401:Promoter Regions, Genetic
D002273:Carcinogens; D019941:Cyclin-Dependent Kinase Inhibitor p16; D008748:Methylcholanthrene