Use of p53 transgenic mice in the development of cancer models for multiple purposes

The tumor suppressor gene p53 is perhaps the most commonly mutated gene in human cancer, being mutated in a high percentage of colon, breast, skin, bl adder, and many cancers of the aerodigestive tract. Individuals with Li-Fra umeni syndrome, who routinely have a germline mutation in the p53 tumor sup pressor gene, are at high risk for lung cancer, confirming its intimate rol e in lung tumorigenesis in humans. In contrast, the majority of chemically induced or spontaneous cancers in rodents do not contain mutations in p53. Therefore, we examined a transgenic mouse that contains a dominant negative mutation (Arg135Val) in the p53 gene placed under the control of its own e ndogenous promoter. The resulting mice have 3 copies of the mutated transge ne as well as 2 normal p53 alleles. In the chemical carcinogenesis studies, we employed mice containing the mutated p53 gene to examine for carcinogen susceptibility. We found that mice with the p53 mutation, on an A/J F1 bac kground, were more susceptible to a number of potential lung carcinogens, i ncluding N-methyl-N-nitrosourea (MNU) and the known tobacco carcinogens 4-( methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo(a)pyrene (BP). Mice with a mutant p53 developed larger tumors and roughly 3 times as many tumors, emphasizing the potential effects of a p53 mutation both on tumor i nitiation and progression. In addition, we examined 2 nonlung carcinogens, 1,2-dimethylhydrazine (DMH), a colon carcinogen, and N-butyl-N-(4-hydroxybu tyl)-nitrosamine (OHBBN), a bladder carcinogen. Interestingly a germline p5 3 mutation increased the incidence of DMH-induced colon, lung, hepatic, and uterine tumors, while having limited effects on OHBBN-induced bladder tumo rs. Because of its heightened susceptibility we are examining the use of th is model in smoke-induced tumorigenesis in A/J mice as well. Employing the lung adenomas induced by NNK, we found that mice with or without a p53 muta tion were equally susceptible to the chemopreventive effects of dexamethaso ne plus myo-inisitol and green tea. The tumors, which arise in a highly rep roducible manner in p53 transgenic mice following carcinogen treatment, hav e mutations in both p53 and the K-ras oncogene. Thus, this model appears us eful for examining for potential chemotherapeutic agents, p53 mutated or wi ld-type mice were equally susceptible to the therapeutic effects of Taxol o r Adriamycin. Interestingly, piroxicam was similarly effective in inhibitin g colon tumor formation by DMH in mice with or without a mutation in the p5 3 tumor suppressor gene. In contrast, lung and uterine tumors developing in these mice were not susceptible to the chemopreventive effects of piroxica m. In summary, mice with mutations in the p53 tumor suppressor gene appear to be particularly applicable for basic mechanistic studies, for screening for potential carcinogens, and for screening for chemopreventive or chemoth erapeutic agents.