title: Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity.
abstract: The recent discovery that normal and neoplastic epithelial cells re-enter the stem cell state raised the intriguing possibility that the aggressiveness of carcinomas derives not from their existing content of cancer stem cells (CSCs) but from their proclivity to generate new CSCs from non-CSC populations. Here, we demonstrate that non-CSCs of human basal breast cancers are plastic cell populations that readily switch from a non-CSC to CSC state. The observed cell plasticity is dependent on ZEB1, a key regulator of the epithelial-mesenchymal transition. We find that plastic non-CSCs maintain the ZEB1 promoter in a bivalent chromatin configuration, enabling them to respond readily to microenvironmental signals, such as TGFβ. In response, the ZEB1 promoter converts from a bivalent to active chromatin configuration, ZEB1 transcription increases, and non-CSCs subsequently enter the CSC state. Our findings support a dynamic model in which interconversions between low and high tumorigenic states occur frequently, thereby increasing tumorigenic and malignant potential.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. chaffer@wi.mit.edu
authors.forename: Christine L
authors.initials: CL
authors.lastname: Chaffer
authors.forename: Nemanja D
authors.initials: ND
authors.lastname: Marjanovic
authors.forename: Tony
authors.initials: T
authors.lastname: Lee
authors.forename: George
authors.initials: G
authors.lastname: Bell
authors.forename: Celina G
authors.initials: CG
authors.lastname: Kleer
authors.forename: Ferenc
authors.initials: F
authors.lastname: Reinhardt
authors.forename: Ana C
authors.initials: AC
authors.lastname: D'Alessio
authors.forename: Richard A
authors.initials: RA
authors.lastname: Young
authors.forename: Robert A
authors.initials: RA
authors.lastname: Weinberg
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D002843:Chromatin / Q000378:metabolism*; D004847:Epithelial Cells / Q000473:pathology; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D002843:Chromatin; D018398:Homeodomain Proteins; D018960:Hyaluronan Receptors; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1