| Literature DB >> 28394329 |
Anne-Pierre Morel1,2, Christophe Ginestier3, Roxane M Pommier1,2, Olivier Cabaud3, Emmanuelle Ruiz1,2, Julien Wicinski3, Mojgan Devouassoux-Shisheboran1,2,4, Valérie Combaret5, Pascal Finetti3, Christelle Chassot1,2, Christiane Pinatel1,2, Frédérique Fauvet1,2, Pierre Saintigny1,2, Emilie Thomas6, Caroline Moyret-Lalle1,2, Joël Lachuer1,2,7, Emmanuelle Despras8, Jean-Luc Jauffret9, François Bertucci3, Jérôme Guitton10, Anne Wierinckx1,2,7, Qing Wang5, Nina Radosevic-Robin11, Frédérique Penault-Llorca11, David G Cox1,2, Frédéric Hollande12, Stéphane Ansieau1,2, Julie Caramel1,2, Daniel Birnbaum3, Arnaud M Vigneron1,2, Agnès Tissier1,2, Emmanuelle Charafe-Jauffret3, Alain Puisieux1,2.
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.Entities:
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Year: 2017 PMID： 28394329 DOI： 10.1038/nm.4323
Source DB: PubMed Journal: Nat Med ISSN： 1078-8956 Impact factor: 53.440