title: A Transposon-based Analysis RevealsRASA1Is Involved in Triple-Negative Breast Cancer.
abstract: RAS genes are mutated in 20% of human tumors, but these mutations are very rare in breast cancer. Here, we used a mouse model to generate tumors upon activation of a mutagenic T2Onc2 transposon via expression of a transposase driven by the keratin K5 promoter in a p53+/-background. These animals mainly developed mammary tumors, most of which had transposon insertions in one of two RASGAP genes, neurofibromin1 (Nf1) and RAS p21 protein activator (Rasa1). Immunohistochemical analysis of a collection of human breast tumors confirmed that low expression of RASA1 is frequent in basal (triple-negative) and estrogen receptor negative tumors. Bioinformatic analysis of human breast tumors in The Cancer Genome Atlas database showed that althoughRASA1mutations are rare, allelic loss is frequent, particularly in basal tumors (80%) and in association withTP53mutation. Inactivation ofRASA1in MCF10A cells resulted in the appearance of a malignant phenotype in the context of mutated p53. Our results suggest that alterations in the Ras pathway due to the loss of negative regulators of RAS may be a common event in basal breast cancer.Cancer Res; 77(6); 1357-68. ©2017 AACR.
authors.affiliation: Molecular Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT)/CIBERONC, Madrid, Spain.|Biomedical Research Institute I+12, 12 de Octubre University Hospital, Madrid, Spain.
authors.forename: Cristian
authors.initials: C
authors.lastname: Suárez-Cabrera
authors.affiliation: Molecular Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT)/CIBERONC, Madrid, Spain.
authors.forename: Rita M
authors.initials: RM
authors.lastname: Quintana
authors.affiliation: Department of Veterinary Clinical Sciences, Faculty of Veterinary Medicine, University of Santiago de Compostela, Lugo, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Bravo
authors.affiliation: Molecular Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT)/CIBERONC, Madrid, Spain.|Biomedical Research Institute I+12, 12 de Octubre University Hospital, Madrid, Spain.
authors.forename: M Llanos
authors.initials: ML
authors.lastname: Casanova
authors.affiliation: Molecular Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT)/CIBERONC, Madrid, Spain.|Biomedical Research Institute I+12, 12 de Octubre University Hospital, Madrid, Spain.
authors.forename: Angustias
authors.initials: A
authors.lastname: Page
authors.affiliation: Molecular Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT)/CIBERONC, Madrid, Spain.|Biomedical Research Institute I+12, 12 de Octubre University Hospital, Madrid, Spain.
authors.forename: Josefa P
authors.initials: JP
authors.lastname: Alameda
authors.affiliation: Molecular Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT)/CIBERONC, Madrid, Spain.|Biomedical Research Institute I+12, 12 de Octubre University Hospital, Madrid, Spain.
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Paramio
authors.affiliation: Department of Pathology, 12 de Octubre University Hospital, Madrid, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Maroto
authors.affiliation: Department of Pathology, 12 de Octubre University Hospital, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Salamanca
authors.affiliation: Department of Anatomy and Cell Biology, Roy J. & Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Dupuy
authors.affiliation: Molecular Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT)/CIBERONC, Madrid, Spain. manuel.navarro@ciemat.es a.ramirez@ciemat.es.|Biomedical Research Institute I+12, 12 de Octubre University Hospital, Madrid, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Ramírez
authors.affiliation: Molecular Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT)/CIBERONC, Madrid, Spain. manuel.navarro@ciemat.es a.ramirez@ciemat.es.|Biomedical Research Institute I+12, 12 de Octubre University Hospital, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Navarro
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004251:DNA Transposable Elements / Q000235:genetics*; D005260:Female; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009367:Neoplasm Staging; D011379:Prognosis; D019895:Transposases / Q000502:physiology*; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D020729:p120 GTPase Activating Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D004251:DNA Transposable Elements; C557248:RASA1 protein, human; D016159:Tumor Suppressor Protein p53; D020729:p120 GTPase Activating Protein; D019895:Transposases; C494471:sleeping beauty transposase, human