Poised Chromatin at the ZEB1 Promoter Enables Breast Cancer Cell Plasticity and Enhances Tumorigenicity

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 popula...

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Bibliographic Details
Published in:Cell 2013-07, Vol.154 (1), p.61-74
Main Authors: Chaffer, Christine L., Marjanovic, Nemanja D., Lee, Tony, Bell, George, Kleer, Celina G., Reinhardt, Ferenc, D’Alessio, Ana C., Young, Richard A., Weinberg, Robert A.
Format: Article
Language:English
Subjects:
Animals
Breast Neoplasms - genetics
Breast Neoplasms - pathology
Chromatin - metabolism
Epithelial Cells - pathology
Gene Knockdown Techniques
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Humans
Hyaluronan Receptors - metabolism
Mice
Mice, Inbred NOD
Mice, SCID
MicroRNAs - metabolism
Neoplastic Stem Cells - metabolism
Neoplastic Stem Cells - pathology
Promoter Regions, Genetic
Transcription Factors - genetics
Transcription Factors - metabolism
Transforming Growth Factor beta - metabolism
Zinc Finger E-box-Binding Homeobox 1
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Summary: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. [Display omitted] •Basal breast cancer non-CSCs are plastic populations that can generate CSCs de novo•ZEB1 drives non-CSC to CSC plasticity•Basal non-CSCs maintain ZEB1 in poised (bivalent) chromatin configuration•Poised ZEB1 promoter more readily responds to the microenvironment Nonaggressive cells in basal, but not lumenal, breast cancers exist in a poised state, ready to switch to an aggressive cancer stem cell state in response to appropriate microenvironmental stimuli, a plasticity that may promote tumorigenicity in basal compared to lumenal breast cancers.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2013.06.005