Poised Chromatin at the ZEB1 Promoter Enables Breast Cancer Cell Plasticity and Enhances Tumorigenicity
Author(s)
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.; Young, Richard A.; Weinberg, Robert A; ... Show more Show less
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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.
Date issued
2013-07Department
Massachusetts Institute of Technology. Department of Biology; Whitehead Institute for Biomedical Research; Koch Institute for Integrative Cancer Research at MITJournal
Cell
Publisher
Elsevier
Citation
Chaffer, Christine L., Nemanja D. Marjanovic, Tony Lee, George Bell, Celina G. Kleer, Ferenc Reinhardt, Ana C. D'Alessio, Richard A. Young, and Robert A. Weinberg. "Poised Chromatin at the ZEB1 Promoter Enables Breast Cancer Cell Plasticity and Enhances Tumorigenicity." Cell 154:1 (3 July 2013), pp. 61-74.
Version: Author's final manuscript
ISSN
00928674