RT Journal Article SR Electronic T1 MYC-driven epigenetic reprogramming favors the onset of tumorigensis by inducing a stem cell-like state JF bioRxiv FD Cold Spring Harbor Laboratory SP 241042 DO 10.1101/241042 A1 Vittoria Poli A1 Luca Fagnocchi A1 Alessandra Fasciani A1 Alessandro Cherubini A1 Stefania Mazzoleni A1 Sara Ferrillo A1 Annarita Miluzio A1 Gabriella Gaudioso A1 Valentina Vaira A1 Alice Turdo A1 Miriam Giaggianesi A1 Aurora Chinnici A1 Elisa Lipari A1 Silvio Bicciato A1 Silvano Bosari A1 Matilde Todaro A1 Alessio Zippo YR 2017 UL http://biorxiv.org/content/early/2017/12/29/241042.abstract AB Breast cancer consists of highly heterogeneous tumors, whose cell of origin and driver oncogenes resulted 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. Over-expression 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.