title: Comparative oncogenomics implicates the neurofibromin 1 gene (NF1) as a breast cancer driver.
abstract: Identifying genomic alterations driving breast cancer is complicated by tumor diversity and genetic heterogeneity. Relevant mouse models are powerful for untangling this problem because such heterogeneity can be controlled. Inbred Chaos3 mice exhibit high levels of genomic instability leading to mammary tumors that have tumor gene expression profiles closely resembling mature human mammary luminal cell signatures. We genomically characterized mammary adenocarcinomas from these mice to identify cancer-causing genomic events that overlap common alterations in human breast cancer. Chaos3 tumors underwent recurrent copy number alterations (CNAs), particularly deletion of the RAS inhibitor Neurofibromin 1 (Nf1) in nearly all cases. These overlap with human CNAs including NF1, which is deleted or mutated in 27.7% of all breast carcinomas. Chaos3 mammary tumor cells exhibit RAS hyperactivation and increased sensitivity to RAS pathway inhibitors. These results indicate that spontaneous NF1 loss can drive breast cancer. This should be informative for treatment of the significant fraction of patients whose tumors bear NF1 mutations.
authors.affiliation: Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Marsha D
authors.initials: MD
authors.lastname: Wallace
authors.forename: Adam D
authors.initials: AD
authors.lastname: Pfefferle
authors.forename: Lishuang
authors.initials: L
authors.lastname: Shen
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: McNairn
authors.forename: Ethan G
authors.initials: EG
authors.lastname: Cerami
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Fallon
authors.forename: Vera D
authors.initials: VD
authors.lastname: Rinaldi
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Southard
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.forename: John C
authors.initials: JC
authors.lastname: Schimenti
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics*; D002478:Cells, Cultured; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000209:etiology / Q000235:genetics*; D051379:Mice; D025542:Neurofibromin 1 / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D025542:Neurofibromin 1; D018631:ras Proteins