6533b856fe1ef96bd12b30ca
RESEARCH PRODUCT
MYC-driven epigenetic reprogramming favors the onset of tumorigenesis by inducing a stem cell-like state
Alessandra FascianiGabriella GaudiosoGabriella GaudiosoAnnarita MiluzioAlessandro CherubiniSara FerrilloElisa LipariValentina VairaValentina VairaStefania MazzoleniAlessio ZippoAlessio ZippoSilvio BicciatoVittoria PoliMiriam GaggianesiAlice TurdoSilvano BosariSilvano BosariAurora ChinniciMatilde TodaroLuca FagnocchiLuca Fagnocchisubject
0301 basic medicineCarcinogenesisScienceGeneral Physics and AstronomyBreast NeoplasmsMice SCIDTumor initiationBiologyBreast cancer MYC Tumorigenesismedicine.disease_causeArticleGeneral Biochemistry Genetics and Molecular BiologyEpigenesis GeneticProto-Oncogene Proteins c-mycMice03 medical and health sciencesCell Line TumormedicineAnimalsHumansEpigeneticslcsh:ScienceEnhancerTranscription factorRegulation of gene expressionMultidisciplinaryQGeneral ChemistryCellular ReprogrammingCell biologyGene Expression Regulation NeoplasticEnhancer Elements Genetic030104 developmental biologyNeoplastic Stem CellsFemalelcsh:QStem cellCarcinogenesisReprogrammingdescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2018-03-01 |