title: Molecular alterations and lung tumors in p53 mutant mice exposed to cigarette smoke.
abstract: Mutations and deletions in p53 are the most common genetic lesions in human cancer,and an extraordinarily high incidence of lung cancer occurs in smokers suffering from Li-Fraumeni syndrome, which is characterized by germ-line inactivation of one p53 allele. In contrast, p53 mutations are infrequent in lung tumors formed in A/J mice. Moreover, despite the dominant role of cigarette smoke in the epidemiology of human lung cancer, it is very difficult to reproduce the lung tumorigenicity of this complex mixture in animal models. We used a transgenic mouse with a dominant-negative p53 mutation to examine the effects of a mutant p53 on smoke-induced lung carcinogenesis in mice. p53 mutant (UL53-3 x A/J)F(1) mice of both genders and their wild-type (wt) littermate controls were exposed whole-body to environmental cigarette smoke (ECS) for up to 9.5 months. Untreated mutant mice of both genders underwent an early stimulus of bronchial cell proliferation, and an age-related formation of DNA adducts in lung and heart. In males, there was an age-related increase of micronucleated normochromatic erythrocytes in peripheral blood and an impairment of body weight gain. These findings underscore a physiological protective role of p53 in wt A/J mice. The response of wt and mutant mice to ECS was similar in terms of oxidative DNA damage in lung and heart, proliferation of the bronchial epithelium, and levels of p53 oncoprotein, as assessed after exposure for 28 days. In contrast, ECS-exposed mutant mice underwent a lower induction of apoptosis in bronchial epithelium, a greater formation of DNA adducts in lung and heart, and a more intense cytogenetic damage, shown by a higher frequency of micronuclei in pulmonary alveolar macrophages and in peripheral blood normochromatic erythrocytes. Interestingly, at the end of the experiment, DNA adducts were not repaired in either wt or mutant mice after discontinuing exposure to ECS for 1 week. A weak but significant increase of lung tumor incidence and multiplicity was induced in p53 mutant (UL53-3 x A/J)F(1) mice after exposure to ECS for either 5 months, followed by recovery in air for 4.5 months, or 9.5 continuative months. Conversely, no tumorigenic effect was observed in their wt littermate controls, carrying a 99.9% A/J background and 5% FVB genome. This contrasts with the weakly positive results obtained in previous studies using wt A/J mice. Thus, in agreement with the results of previous lung tumorigenicity studies performed with the smoke carcinogens benzo(a)pyrene and 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone, (UL53-3 x A/J)F(1) mice carrying a mutant p53 transgene appear to be more sensitive to ECS than the corresponding wt littermate controls. These findings provide evidence that p53 mutations play a role in smoke-related carcinogenesis not only in humans but also in A/J mice.
authors.affiliation: Department of Health Sciences, University of Genoa, I-16132 Genoa, Italy. sdf@unige.it
authors.forename: Silvio
authors.initials: S
authors.lastname: De Flora
authors.forename: Roumen M
authors.initials: RM
authors.lastname: Balansky
authors.forename: Francesco
authors.initials: F
authors.lastname: D'Agostini
authors.forename: Alberto
authors.initials: A
authors.lastname: Izzotti
authors.forename: Anna
authors.initials: A
authors.lastname: Camoirano
authors.forename: Carlo
authors.initials: C
authors.lastname: Bennicelli
authors.forename: Zhongqiu
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yian
authors.initials: Y
authors.lastname: Wang
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Lubet
authors.forename: Ming
authors.initials: M
authors.lastname: You
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D003043:Cocarcinogenesis; D018736:DNA Adducts / Q000378:metabolism; D004249:DNA Damage; D004195:Disease Models, Animal; D005260:Female; D016158:Genes, p53 / Q000235:genetics / Q000502:physiology*; D020022:Genetic Predisposition to Disease; D008175:Lung Neoplasms / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008822:Mice, Transgenic; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015430:Weight Gain
chemical_list: D018736:DNA Adducts; D012906:Smoke; D016159:Tumor Suppressor Protein p53