This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wang, Y. Articles by You, M. Search for Related Content PubMed PubMed Citation Articles by Wang, Y. Articles by You, M.

Mice with Alterations in Both p53 and Ink4a/Arf Display a Striking Increase in Lung Tumor Multiplicity and Progression

Differential Chemopreventive Effect of Budesonide in Wild-type and Mutant A/J Mice¹

Department of Surgery and The Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri 63110 [Y. W., Z. Z., E. K., M. Y.], and Chemoprevention Agent Development Research Group, National Cancer Institute, Bethesda, Maryland 20892 [R. A. L.]

p53 transgenic mice carrying a dominant negative mutation were crossed with Ink4A/Arf heterozygous-deficient mice to investigate whether there is a synergy between these two germ-line mutations in promoting carcinogen-induced lung tumor progression in mice. Mice with a p53 dominant negative mutation and Ink4A/Arf heterozygous deficiency exhibited >20-fold increase in tumor volume compared with 4-fold increase in Ink4A/Arf heterozygous-deficient mice and a 9-fold increase in mice with only the p53 dominant negative mutation. The effect of Ink4A/Arf heterozygous deficiency on lung tumor progression occurred late in the carcinogenesis process (>30 weeks after carcinogen treatment). In addition, most of the lung tumors (80%) from mice with a p53 mutation and deletion of Ink4A/Arf were lung adenocarcinomas. In contrast, lung adenocarcinomas were seen in <10% of the lung tumors from the wild-type mice and 50% of the lung tumors from Ink4a/Arf heterozygous-deficient or p53 mutant mice. These results indicate a significant synergistic interaction between the presence of a mutant p53 transgene and the Ink4A/Arf deletion during lung tumor progression (P < 0.01). The usefulness of this new mouse model in lung cancer chemoprevention was examined. The chemopreventive efficacy of budesonide was examined in wild-type mice, mice with Ink4A/Arf heterozygous deficiency, mice with a mutation in the p53 gene, or mice with both a mutation in the p53 gene and deletion in the Ink4A/Arf locus. Mice treated with budesonide displayed an average of 90% inhibition of lung tumor progression in a standard 18-week chemoprevention assay, regardless of p53 and/or Ink4A/Arf status. However, the efficacy of budesonide against lung tumor progression decreased from 94 to 77% (P = 0.07) in mice with alterations in both p53 and Ink4A/Arf in a 40-week chemoprevention assay. Similarly, when mice bearing established lung adenomas were treated with budesonide, genotype-dependent differential effects of budesonide in wild-type and mutant mice were clearly revealed with a 82, 64, 45, and 33% decrease in tumor volume in wild-type mice, p53^+/+Ink4a/Arf^+/- mice, p53^+/-Ink4a/Arf^+/+ mice, and p53^+/-Ink4a/Arf^+/-, respectively. Thus, mutant mice with alterations in p53 and/or Ink4A/Arf exhibited a significant resistance to chemoprevention by budesonide. Because p53 and Ink4a/Arf mutations are the most prevalent mutations in human lung cancers, the effectiveness of chemopreventive agents on the mutant A/J mice containing alterations with p53 and Ink4a/Arf is the best preclinical estimate of their efficacy in humans. Thus, the mutant A/J mouse model should prove useful for chemoprevention studies.

This article has been cited by other articles:

				R. M. van den Berg, H. van Tinteren, N. van Zandwijk, C. Visser, A. Pasic, C. Kooi, T. G. Sutedja, P. Baas, K. Grunberg, W. J. Mooi, et al. The Influence of Fluticasone Inhalation on Markers of Carcinogenesis in Bronchial Epithelium Am. J. Respir. Crit. Care Med., May 15, 2007; 175(10): 1061 - 1065. [Abstract] [Full Text] [PDF]

				F. S. Alyaqoub, L. Tao, P. M. Kramer, V. E. Steele, R. A. Lubet, W. T. Gunning, and M. A. Pereira Prevention of mouse lung tumors and modulation of DNA methylation by combined treatment with budesonide and R115777 (ZarnestraMT) Carcinogenesis, January 1, 2007; 28(1): 124 - 129. [Abstract] [Full Text] [PDF]

				F. S. Alyaqoub, L. Tao, P. M. Kramer, V. E. Steele, R. A. Lubet, W. T. Gunning, and M. A. Pereira Prevention of mouse lung tumors and modulation of DNA methylation by combined treatment with budesonide and R115777 (ZarnestraMT) Carcinogenesis, December 1, 2006; 27(12): 2442 - 2447. [Abstract] [Full Text] [PDF]

				Z. Zhang, Y. Wang, R. Yao, R. A. Lubet, and M. You p53 Transgenic Mice Are Highly Susceptible to 4-Nitroquinoline-1-Oxide-Induced Oral Cancer Mol. Cancer Res., June 1, 2006; 4(6): 401 - 410. [Abstract] [Full Text] [PDF]

				R. Balansky, F. D'Agostini, G. Ganchev, A. Izzotti, B. Di Marco, R. A. Lubet, N. Zanesi, C. M. Croce, and S. De Flora Influence of FHIT on benzo[a]pyrene-induced tumors and alopecia in mice: Chemoprevention by budesonide and N-acetylcysteine PNAS, May 16, 2006; 103(20): 7823 - 7828. [Abstract] [Full Text] [PDF]

				R. Meuwissen and A. Berns Mouse models for human lung cancer Genes & Dev., March 15, 2005; 19(6): 643 - 664. [Abstract] [Full Text] [PDF]

				L. J. Hofseth The adaptive imbalance to genotoxic stress: genome guardians rear their ugly heads Carcinogenesis, October 1, 2004; 25(10): 1787 - 1793. [Abstract] [Full Text] [PDF]

				S. Lam, J. C. leRiche, A. McWilliams, C. MacAulay, Y. Dyachkova, E. Szabo, J. Mayo, R. Schellenberg, A. Coldman, E. Hawk, et al. A Randomized Phase IIb Trial of Pulmicort Turbuhaler (Budesonide) in People with Dysplasia of the Bronchial Epithelium Clin. Cancer Res., October 1, 2004; 10(19): 6502 - 6511. [Abstract] [Full Text] [PDF]

				R. A. Lubet, Z. Zhang, Y. Wang, and M. You Chemoprevention of Lung Cancer in Transgenic Mice Chest, May 1, 2004; 125(5_suppl): 144S - 147S. [Full Text] [PDF]

				J. R. Garbow, Z. Zhang, and M. You Detection of Primary Lung Tumors in Rodents by Magnetic Resonance Imaging Cancer Res., April 15, 2004; 64(8): 2740 - 2742. [Abstract] [Full Text] [PDF]