TY - JOUR
T1 - MYC-driven epigenetic reprogramming favors the onset of tumorigenesis by inducing a stem cell-like state
AU - Poli, Vittoria
AU - Fagnocchi, Luca
AU - Fasciani, Alessandra
AU - Cherubini, Alessandro
AU - Mazzoleni, Stefania
AU - Ferrillo, Sara
AU - Miluzio, Annarita
AU - Gaudioso, Gabriella
AU - Vaira, Valentina
AU - Turdo, Alice
AU - Giaggianesi, Miriam
AU - Chinnici, Aurora
AU - Lipari, Elisa
AU - Bicciato, Silvio
AU - Bosari, Silvano
AU - Todaro, Matilde
AU - Zippo, Alessio
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-018-03264-2
DO - 10.1038/s41467-018-03264-2
M3 - Article
AN - SCOPUS:85044003494
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1024
ER -