Carcinogen inactivation of tumor suppressor genes in p53 haploinsufficient mice.

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Inactivation of both alleles of a gene by mutation or loss of heterozygosity due to genomic instability in the development of a cancer is required for that gene to be characterized as a tumor suppressor gene. This observation has become a hallmark for human cancers; particularly for the p53 tumor suppressor gene. The wild type p53 tumor suppressor protein suppresses the development of cancer in human and mice and is critical to the normal cell functions of cell cycle and maintenance of genomic stability. The mechanisms of p53 inactivation in human or mouse cancers are poorly understood. Exposure to endogenous or exogenous carcinogens under conditions of susceptiblity are believed to be involved and significantly increase risk for the development of cancer. Prospective identification of naturally occuring or synthetic environmental chemicals with carcinogenic potential of presumed risk to humans has primarily been carried out using two year rodent cancer bioassays. We, and others, have recently demonstrated that genetically altered mice heterozygous for a functional p53 allele rapidly develop cancer when exposed to chemical and physical carcinogens. These new short term cancer bioassays offer the promise of both reducing the resources required for prospective identification of potential carcinogens and providing a mechanistic basis for cancer induction. Demonstration of a mechanistic basis for cancer induction in mice similar to that observed in human cancer greatly strengthens the premise that a rodent chemical carcinogen may also be a potential human carcinogen. Using a series of rodent carcinogens (benzene, p-cresidine, phenolpthalein)and the human carcinogens (benzene and mephalan) we have been able to demonstrate that tumors of mesenchymal origin (lymphoma, sarcoma, etc.) primarily show a high frequency of the rapid loss of the remaining p53 functional allele, wheras carcinomas of the epidermis and bladder primarily show potential inactivating mutations in exon 5 of the functional p53 allele. These observations are critical to the argument that rapid short term cancer bioassays can rapidly prospectively identify carcinogens of potential significance to exposed humans. Thus, public health strategies for intervention and prevention may be developed to minimize exposure and risk.