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Nat Med. 2017 May;23(5):568-578. doi: 10.1038/nm.4323. Epub 2017 Apr 10.

A stemness-related ZEB1-MSRB3 axis governs cellular pliancy and breast cancer genome stability.

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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.
Université Aix Marseille, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Molecular Oncology, Equipe labellisée Ligue Contre le Cancer, Marseille, France.
Hôpital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France.
Centre Léon Bérard, Lyon, France.
Fondation Synergie Lyon Cancer, Centre Léon Bérard, Lyon, France.
ProfileXpert, Bron, France.
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.
Clinique Phenicia, Marseille, France.
Université de Lyon, Université Claude Bernard Lyon 1, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Pierre Bénite, France.
Department of Pathology, Jean Perrin Cancer Center and ERTICa Research Group, University of Auvergne, Clermont-Ferrand, France.
Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.


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.

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