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(Chest. 2004;125:85S-86S.)
© 2004 American College of Chest Physicians

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 and Mitchell Friedman, MD, FCCP

* 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{at}tulane.edu

Key Words: asbestos • lung cancer • p53

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.


   Footnotes
 
Abbreviation: SPC = surfactant protein C

This research was supported by the Louisiana Health Excellence Fund.


   References
TOP
 References
 

  1. Greenblatt, MS, Bennett, WP, Hollstein, M, et al (1994) Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 54,4855-4878[Free Full Text]
  2. Dragani, TA, Manenti, G, Pierotti, MA Genetics of murine lung tumors. Adv Cancer Res 1995;67,83-112[ISI][Medline]
  3. Morris, GF, Hoyle, GW, Athas, GB, et al Lung-specific expression in mice of a dominant negative mutant form of the p53 tumor suppressor protein. J La State Med Soc 1998;150,179-185[Medline]
  4. Ghosh, S, Mendoza, T, Ortiz, LA, et al Bleomycin sensitivity of mice expressing dominant negative p53 in the lung epithelium. Am J Respir Crit Care Med 2002;166,890-897[Abstract/Free Full Text]
  5. Mishra, A, Liu, JY, Brody, AR, et al Inhaled asbestos fibers induce p53 expression in the rat lung. Am J Respir Cell Mol Biol 1997;16,479-485[Abstract]
  6. Selikoff, IJ, Hammond, EC, Seidman, H Mortality experience of insulation workers in the United States and Canada, 1943–1976. Ann N Y Acad Sci 1979;330,473-490[Medline]




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