A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors
- David Dankort1,
- Elena Filenova1,
- Manuel Collado3,
- Manuel Serrano3,
- Kirk Jones2, and
- Martin McMahon1,4
- 1 Cancer Research Institute, Department of Cellular and Molecular Pharmacology, University of California, San Francisco Comprehensive Cancer Center, San Francisco, California 94143, USA;
- 2 Department of Pathology, University of California, San Francisco Comprehensive Cancer Center, San Francisco, California 94143, USA;
- 3 Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain
Abstract
Mutationally activated BRAFV600E (BRAFVE) is detected in ∼6% of human malignancies and promotes sustained MEK1/2–ERK1/2 pathway activation. We have designed BRafCA mice to express normal BRaf prior to Cre-mediated recombination after which BRafVE is expressed at physiological levels. BRafCA mice infected with an Adenovirus expressing Cre recombinase developed benign lung tumors that only rarely progressed to adenocarcinoma. Moreover, BRafVE-induced lung tumors were prevented by pharmacological inhibition of MEK1/2. BRafVE expression initially induced proliferation that was followed by growth arrest bearing certain hallmarks of senescence. Consistent with Ink4a/Arf and TP53 tumor suppressor function, BRafVE expression combined with mutation of either locus led to cancer progression.
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Footnotes
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↵4 Corresponding author.
↵4 E-MAIL mcmahon{at}cc.ucsf.edu; FAX (415) 502-3179.
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Supplemental material is available at http://www.genesdev.org.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1516407
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- Received November 27, 2006.
- Accepted January 4, 2007.
- Copyright © 2007, Cold Spring Harbor Laboratory Press