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Development of Lung Tumors in Mutant p53-Expressing Mice After Inhalation Exposure to Asbestos*

Gilbert F. Morris, PhD; Amy R. Notwick, BS; Odile David, MD; Cesar Fermin, PhD; Arnold R. Brody, PhD; Mitchell Friedman, MD, FCCP
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*From the Departments of Pathology (Drs. Morris, David, Fermin, and Brody, and Ms. Notwick) and Medicine (Dr. Friedman), Program in Lung Biology, Tulane University Medical Center, New Orleans, LA.

Correspondence to: Gilbert F. Morris, PhD, Department of Pathology, SL-79, Tulane University Medical Center, 1430 Tulane Ave, New Orleans, LA 70112; e-mail: gmorris2@tulane.edu



Chest. 2004;125(5_suppl):85S-86S. doi:10.1378/chest.125.5_suppl.85S
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The gene encoding the p53 tumor suppressor protein is commonly mutated in many human cancers, including lung cancer,1 but p53 mutations are relatively rare in murine lung tumors induced by carcinogen exposures.2 To model the pathogenesis of human lung cancers in mice, we disrupted wild-type p53 activities by transgenically expressing a dominant-negative form of p53 specifically in the lung epithelium using the human surfactant protein C (SPC) promoter, SPC-DNp53 mice.3 Distinct responses to fibrogenic agents have indicated that the transgene has altered the phenotype of SPC-DNp53 mice.4 However, the low incidence and delayed onset of lung tumor development in unexposed SPC-DNp53 mice imply that the oncogenic p53 transgene requires additional activities to complete the process of neoplastic conversion. Inhaled asbestos activates p53 expression at the sites of fiber deposition,5 and epidemiologic evidence indicates that exposure to asbestos increases the risk of lung cancer about fivefold.6 We postulate that the p53-mediated response to asbestos protects against the development of lung tumors. In accord with this postulate, a single exposure to an aerosol of asbestos for 5 h produced a significantly higher incidence of lung tumors in SPC-DNp53 transgenic mice than in simultaneously exposed nontransgenic littermates. These data indicate that compromised p53 function in the lung epithelium cooperates with asbestos in lung tumorigenesis.

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