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Carcinogenesis Advance Access published online on July 28, 2005
Carcinogenesis, doi:10.1093/carcin/bgi190
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received February 7, 2005
Revised July 15, 2005
Accepted July 19, 2005

CARCINOGENESIS

Conditional expression of the mutant Ki-rasG12C allele results in formation of benign lung adenomas: development of a novel mouse lung tumor model

Heather S. Floyd 1, Charles L. Farnsworth 2, Nancy D. Kock 3, Melissa C. Mizesko 4, Joy L. Little 4, Stephanie T. Dance 4, Jeff Everitt 5, Jay Tichelaar 6, Jeffrey A. Whitsett 7, and Mark Steven Miller 4*

1 Department of Cancer Biology, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157; Address as of June 2005: Department of Pathology and Laboratory Sciences, Tulane University Health Sciences Center, New Orleans, LA 700112, USA
2 Cell Signaling Technology, Beverly, MA 01915
3 Department of Comparative Medicine, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157
4 Department of Cancer Biology, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157
5 GlaxoSmithKline, Research Triangle Park, NC 27709
6 Department of Environmental Health Sciences, Division of Toxicology, University of Cincinnati College of Medicine, Cincinnati, OH 45267
7 Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45339, USA

* To whom correspondence should be addressed.
Mark Steven Miller, E-mail: msmiller{at}wfubmc.edu


  Abstract

To determine the effects of expression of mutant Ki-ras on lung tumorigenesis, we developed a bitransgenic mouse model that expresses the human Ki-rasG12C allele in alveolar type II and/or Clara cells in a tetracycline-inducible, lung-specific manner. Expression of Ki-rasG12C caused multiple, small lung tumors over a 12 month time period. Although tumor multiplicity increased upon continued Ki-ras expression, most lung lesions were hyperplasias or well differentiated adenomas. This contrasts to the more severe phenotypes observed in other transgenic mouse models in which different mutant Ki-ras alleles were expressed in the lung. Expression of Ki-rasG12C was associated with a 2-fold increase in the activation of the Ras and Ral signaling pathways and increased phosphorylation of Ras downstream effectors, including Erk, p90 ribosomal S6 kinase, ribosomal S6 protein, p38, and MAPKAPK-2. In contrast, expression of the transgene had no effect on the activation of the JNK and Akt signaling pathways. Withdrawal of DOX for 1 month resulted in almost a complete absence of proliferative pulmonary lesions, suggesting tumor regression in the absence of Ki-ras expression. Mutant Ki-rasG12C expression was sufficient for initial lung tumor transformation, required for maintenance of tumor phenotype, and induced transformation of lung epithelial cells by the activation of multiple effector pathways. These results describe a novel mouse lung tumor model demonstrating benign tumor development in the absence of tumor progression, which will provide a new tool for understanding the early stages of lung tumor pathogenesis.

Keywords: Ki-ras; lung cancer; transgenic mice.
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