MYC-driven epigenetic reprogramming favors the onset of tumorigenesis by inducing a stem cell-like state

Vittoria Poli, Luca Fagnocchi, Alessandra Fasciani, Alessandro Cherubini, Stefania Mazzoleni, Sara Ferrillo, Annarita Miluzio, Gabriella Gaudioso, Valentina Vaira, Alice Turdo, Miriam Gaggianesi, Aurora Chinnici, Elisa Lipari, Silvio Bicciato, Silvano Bosari, Matilde Todaro and Alessio Zippo ()
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Vittoria Poli: University of Trento
Luca Fagnocchi: University of Trento
Alessandra Fasciani: University of Trento
Alessandro Cherubini: Fondazione Istituto Nazionale di Genetica Molecolare “Romeo ed Enrica Invernizzi”
Stefania Mazzoleni: Fondazione Istituto Nazionale di Genetica Molecolare “Romeo ed Enrica Invernizzi”
Sara Ferrillo: Fondazione Istituto Nazionale di Genetica Molecolare “Romeo ed Enrica Invernizzi”
Annarita Miluzio: Fondazione Istituto Nazionale di Genetica Molecolare “Romeo ed Enrica Invernizzi”
Gabriella Gaudioso: Fondazione Istituto Nazionale di Genetica Molecolare “Romeo ed Enrica Invernizzi”
Valentina Vaira: Fondazione Istituto Nazionale di Genetica Molecolare “Romeo ed Enrica Invernizzi”
Alice Turdo: University of Palermo
Miriam Gaggianesi: University of Palermo
Aurora Chinnici: University of Palermo
Elisa Lipari: University of Palermo
Silvio Bicciato: University of Modena and Reggio Emilia
Silvano Bosari: Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico
Matilde Todaro: University of Palermo
Alessio Zippo: University of Trento

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract Breast cancer consists of highly heterogeneous tumors, whose cell of origin and driver oncogenes are difficult to be uniquely defined. Here we report that MYC acts as tumor reprogramming factor in mammary epithelial cells by inducing an alternative epigenetic program, which triggers loss of cell identity and activation of oncogenic pathways. Overexpression of MYC induces transcriptional repression of lineage-specifying transcription factors, causing decommissioning of luminal-specific enhancers. MYC-driven dedifferentiation supports the onset of a stem cell-like state by inducing the activation of de novo enhancers, which drive the transcriptional activation of oncogenic pathways. Furthermore, we demonstrate that the MYC-driven epigenetic reprogramming favors the formation and maintenance of tumor-initiating cells endowed with metastatic capacity. This study supports the notion that MYC-driven tumor initiation relies on cell reprogramming, which is mediated by the activation of MYC-dependent oncogenic enhancers, thus establishing a therapeutic rational for treating basal-like breast cancers.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03264-2

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DOI: 10.1038/s41467-018-03264-2

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