title: Lkb1 loss promotes tumor progression of BRAF(V600E)-induced lung adenomas.
abstract: Aberrant activation of MAP kinase signaling pathway and loss of tumor suppressor LKB1 have been implicated in lung cancer development and progression. Although oncogenic KRAS mutations are frequent, BRAF mutations (BRAF(V600E)) are found in 3% of human non-small cell lung cancers. Contrary to KRAS mutant tumors, BRAF(V600E)-induced tumors are benign adenomas that fail to progess. Interestingly, loss of tumor supressor LKB1 coexists with KRAS oncogenic mutations and synergizes in tumor formation and progression, however, its cooperation with BRAF(V600E) oncogene is unknown. Our results describe a lung cell population in neonates mice where expression of BRAF(V600E) leads to lung adenoma development. Importantly, expression of BRAF(V600E) concomitant with the loss of only a single-copy of Lkb1, overcomes senencence-like features of BRAF(V600E)-mutant adenomas leading malignization to carcinomas. These results posit LKB1 haploinsufficiency as a risk factor for tumor progression of BRAF(V600E) mutated lung adenomas in human cancer patients.
authors.affiliation: Animal Models and Cancer Laboratory, Anatomy Pathology Department, Vall d'Hebron Institut of Research-Autonomous University of Barcelona (VHIR-UAB) Barcelona, Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: González-Sánchez
authors.forename: Juan
authors.initials: J
authors.lastname: Martín-Caballero
authors.forename: Juana María
authors.initials: JM
authors.lastname: Flores
authors.forename: Javier
authors.initials: J
authors.lastname: Hernández-Losa
authors.forename: Javier
authors.initials: J
authors.lastname: Cortés
authors.forename: Roso
authors.initials: R
authors.lastname: Mares
authors.forename: Mariano
authors.initials: M
authors.lastname: Barbacid
authors.forename: Juan A
authors.initials: JA
authors.lastname: Recio
mesh_terms: D055372:AMP-Activated Protein Kinases; D000236:Adenoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D000818:Animals; D000831:Animals, Newborn; D015820:Cadherins / Q000378:metabolism; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics; D018450:Disease Progression; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009857:Oncogenes / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D037721:Pulmonary Surfactant-Associated Protein C / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D015820:Cadherins; D037721:Pulmonary Surfactant-Associated Protein C; D016159:Tumor Suppressor Protein p53; D013629:Tamoxifen; C016601:afimoxifene; D017346:Protein Serine-Threonine Kinases; D048493:Proto-Oncogene Proteins B-raf; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases