title: A stemness-related ZEB1-MSRB3 axis governs cellular pliancy and breast cancer genome stability.
abstract: Chromosomal instability (CIN), a feature of most adult neoplasms from their early stages onward, is a driver of tumorigenesis. However, several malignancy subtypes, including some triple-negative breast cancers, display a paucity of genomic aberrations, thus suggesting that tumor development may occur in the absence of CIN. Here we show that the differentiation status of normal human mammary epithelial cells dictates cell behavior after an oncogenic event and predetermines the genetic routes toward malignancy. Whereas oncogene induction in differentiated cells induces massive DNA damage, mammary stem cells are resistant, owing to a preemptive program driven by the transcription factor ZEB1 and the methionine sulfoxide reductase MSRB3. The prevention of oncogene-induced DNA damage precludes induction of the oncosuppressive p53-dependent DNA-damage response, thereby increasing stem cells' intrinsic susceptibility to malignant transformation. In accord with this model, a subclass of breast neoplasms exhibit unique pathological features, including high ZEB1 expression, a low frequency of TP53 mutations and low CIN.
authors.affiliation: Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Equipe Labellisée Ligue contre le Cancer, Lyon, France.|LabEx DEVweCAN, Université de Lyon, Lyon, France.
authors.forename: Anne-Pierre
authors.initials: AP
authors.lastname: Morel
authors.affiliation: Université Aix Marseille, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Molecular Oncology, Equipe labellisée Ligue Contre le Cancer, Marseille, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Ginestier
authors.affiliation: Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Equipe Labellisée Ligue contre le Cancer, Lyon, France.|LabEx DEVweCAN, Université de Lyon, Lyon, France.
authors.forename: Roxane M
authors.initials: RM
authors.lastname: Pommier
authors.affiliation: Université Aix Marseille, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Molecular Oncology, Equipe labellisée Ligue Contre le Cancer, Marseille, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Cabaud
authors.affiliation: Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Equipe Labellisée Ligue contre le Cancer, Lyon, France.|LabEx DEVweCAN, Université de Lyon, Lyon, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Ruiz
authors.affiliation: Université Aix Marseille, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Molecular Oncology, Equipe labellisée Ligue Contre le Cancer, Marseille, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Wicinski
authors.affiliation: Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Equipe Labellisée Ligue contre le Cancer, Lyon, France.|LabEx DEVweCAN, Université de Lyon, Lyon, France.|Hôpital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France.
authors.forename: Mojgan
authors.initials: M
authors.lastname: Devouassoux-Shisheboran
authors.affiliation: Centre Léon Bérard, Lyon, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Combaret
authors.affiliation: Université Aix Marseille, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Molecular Oncology, Equipe labellisée Ligue Contre le Cancer, Marseille, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Finetti
authors.affiliation: Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Equipe Labellisée Ligue contre le Cancer, Lyon, France.|LabEx DEVweCAN, Université de Lyon, Lyon, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Chassot
authors.affiliation: Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Equipe Labellisée Ligue contre le Cancer, Lyon, France.|LabEx DEVweCAN, Université de Lyon, Lyon, France.
authors.forename: Christiane
authors.initials: C
authors.lastname: Pinatel
authors.affiliation: Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Equipe Labellisée Ligue contre le Cancer, Lyon, France.|LabEx DEVweCAN, Université de Lyon, Lyon, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Fauvet
authors.affiliation: Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Equipe Labellisée Ligue contre le Cancer, Lyon, France.|LabEx DEVweCAN, Université de Lyon, Lyon, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Saintigny
authors.affiliation: Fondation Synergie Lyon Cancer, Centre Léon Bérard, Lyon, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Thomas
authors.affiliation: Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Equipe Labellisée Ligue contre le Cancer, Lyon, France.|LabEx DEVweCAN, Université de Lyon, Lyon, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Moyret-Lalle
authors.affiliation: Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Equipe Labellisée Ligue contre le Cancer, Lyon, France.|LabEx DEVweCAN, Université de Lyon, Lyon, France.|ProfileXpert, Bron, France.
authors.forename: Joël
authors.initials: J
authors.lastname: Lachuer
authors.affiliation: Université Paris-Sud, CNRS-UMR 8200, Unit of Genetic Stability and Oncogenesis, Equipe Labellisée Ligue contre le Cancer, Institut de Cancérologie Gustave Roussy, Villejuif, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Despras
authors.affiliation: Clinique Phenicia, Marseille, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Jauffret
authors.affiliation: Université Aix Marseille, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Molecular Oncology, Equipe labellisée Ligue Contre le Cancer, Marseille, France.
authors.forename: François
authors.initials: F
authors.lastname: Bertucci
authors.affiliation: Université de Lyon, Université Claude Bernard Lyon 1, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Pierre Bénite, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Guitton
authors.affiliation: Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Equipe Labellisée Ligue contre le Cancer, Lyon, France.|LabEx DEVweCAN, Université de Lyon, Lyon, France.|ProfileXpert, Bron, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Wierinckx
authors.affiliation: Centre Léon Bérard, Lyon, France.
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Pathology, Jean Perrin Cancer Center and ERTICa Research Group, University of Auvergne, Clermont-Ferrand, France.
authors.forename: Nina
authors.initials: N
authors.lastname: Radosevic-Robin
authors.affiliation: Department of Pathology, Jean Perrin Cancer Center and ERTICa Research Group, University of Auvergne, Clermont-Ferrand, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Penault-Llorca
authors.affiliation: Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Equipe Labellisée Ligue contre le Cancer, Lyon, France.|LabEx DEVweCAN, Université de Lyon, Lyon, France.
authors.forename: David G
authors.initials: DG
authors.lastname: Cox
authors.affiliation: Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Frédéric
authors.identifier: http://orcid.org/0000-0002-7046-8392
authors.initials: F
authors.lastname: Hollande
authors.affiliation: Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Equipe Labellisée Ligue contre le Cancer, Lyon, France.|LabEx DEVweCAN, Université de Lyon, Lyon, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Ansieau
authors.affiliation: Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Equipe Labellisée Ligue contre le Cancer, Lyon, France.|LabEx DEVweCAN, Université de Lyon, Lyon, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Caramel
authors.affiliation: Université Aix Marseille, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Molecular Oncology, Equipe labellisée Ligue Contre le Cancer, Marseille, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Birnbaum
authors.affiliation: Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Equipe Labellisée Ligue contre le Cancer, Lyon, France.|LabEx DEVweCAN, Université de Lyon, Lyon, France.
authors.forename: Arnaud M
authors.initials: AM
authors.lastname: Vigneron
authors.affiliation: Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Equipe Labellisée Ligue contre le Cancer, Lyon, France.|LabEx DEVweCAN, Université de Lyon, Lyon, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Tissier
authors.affiliation: Université Aix Marseille, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Molecular Oncology, Equipe labellisée Ligue Contre le Cancer, Marseille, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Charafe-Jauffret
authors.affiliation: Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Equipe Labellisée Ligue contre le Cancer, Lyon, France.|LabEx DEVweCAN, Université de Lyon, Lyon, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Puisieux
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D004249:DNA Damage; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting; D042361:Mammary Glands, Human / Q000166:cytology; D051150:Methionine Sulfoxide Reductases / Q000235:genetics* / Q000378:metabolism; D016688:Mice, Inbred NOD; D008875:Middle Aged; D017382:Reactive Oxygen Species; D060888:Real-Time Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D046888:Tissue Array Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D055815:Young Adult; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D051150:Methionine Sulfoxide Reductases; C524352:MSRB3 protein, human