A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors.
Mutationally activated BRAF(V600E) (BRAF(VE)) is detected in approximately 6% of human malignancies and promotes sustained MEK1/2-ERK1/2 pathway activation. We have designed BRaf(CA) mice to express normal BRaf prior to Cre-mediated recombination after which BRaf(VE) is expressed at physiological levels. BRaf(CA) mice infected with an Adenovirus expressing Cre recombinase developed benign lung tumors that only rarely progressed to adenocarcinoma. Moreover, BRaf(VE)-induced lung tumors were prevented by pharmacological inhibition of MEK1/2. BRaf(VE) expression initially induced proliferation that was followed by growth arrest bearing certain hallmarks of senescence. Consistent with Ink4a/Arf and TP53 tumor suppressor function, BRaf(VE) expression combined with mutation of either locus led to cancer progression.
Dankort
David
D
Cancer Research Institute, Department of Cellular and Molecular Pharmacology, University of California, San Francisco Comprehensive Cancer Center, California 94143, USA.
Filenova
Elena
E
Collado
Manuel
M
Serrano
Manuel
M
Jones
Kirk
K
McMahon
Martin
M
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D008168:Lung / Q000737:chemistry / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048370:MAP Kinase Kinase 2 / Q000032:analysis; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D047428:Protein Kinase Inhibitors; D016159:Tumor Suppressor Protein p53; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482129:Map2k2 protein, mouse