Genetic alterations in mouse lung tumors: implications for cancer chemoprevention.
Specific genetic alterations affecting known tumor suppressor genes and proto-oncogenes occur during mouse lung tumorigenesis. These include mutational activation of the K-ras gene, commonly seen at a frequency of about 80% in both spontaneously occurring and chemically induced adenomas and adenocarcinomas of the lung, suggesting that it is an early event that persists into malignancy. Allelic loss of the p16 tumor suppressor gene also is a frequent event, occurring in about 50% of mouse lung adenocarcinomas, but rarely in lung adenomas, suggesting that it may play a role in malignant conversion or progression of lung tumors. Other genetic alterations detected in mouse lung tumors include reduced expression of Rb and p16, and increased c-myc expression. Alterations of these genes are also common in the genesis of human lung cancer. Genetic linkage analysis to identify human lung cancer susceptibility genes is difficult due to the genetic heterogeneity and exposure to environmental risk factors. The mouse lung tumor model has become a valuable alternative for identifying such genes. Recently, loci responsible for mouse lung tumor susceptibility have been mapped to chromosomes 6, 9, 17, and 19, while those linked to lung tumor resistance have been mapped to chromosomes 4, 11, 12, and 18. Known candidate susceptibility or resistance genes include the K-ras proto-oncogene on chromosome 6, and the p16 tumor suppressor gene on chromosome 4. With evidence of considerable overlap between the genetic alterations that underlie human and mouse lung tumorigenesis, the mouse lung tumor model has been expanded to include pre-clinical screening of chemopreventive agents against human lung cancer. Studies on the modulation of genetic defects in mouse lung tumors by known and potential chemopreventive agents should further the goal of developing an effective prevention and treatment of lung cancer.
Herzog
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Department of Pathology, Medical College of Ohio, Toledo 43614-5806, USA.
Lubet
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You
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D000818:Animals; D018890:Chemoprevention; D004195:Disease Models, Animal; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000517:prevention & control*; D051379:Mice; D009857:Oncogenes; D000090063:Proto-Oncogene Mas