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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| Format: | Article |
| Language: | en_US |
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Elsevier
2016
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| Online Access: | http://hdl.handle.net/1721.1/103883 https://orcid.org/0000-0002-0895-3557 https://orcid.org/0000-0001-8855-8647 |
| _version_ | 1826211633304698880 |
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| author | 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 |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology 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 |
| author_sort | Chaffer, Christine L. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T15:09:04Z |
| format | Article |
| id | mit-1721.1/103883 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:09:04Z |
| publishDate | 2016 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1038832022-09-29T13:02:22Z Poised Chromatin at the ZEB1 Promoter Enables Breast Cancer Cell Plasticity and Enhances Tumorigenicity 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 Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Koch Institute for Integrative Cancer Research at MIT Young, Richard A. Weinberg, Robert A. 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. Advanced Medical Research Foundation (Brookline, Mass.) Breast Cancer Research Foundation National Institutes of Health (U.S.) (NIH grant HG002668) National Institutes of Health (U.S.) (NIH grant CA146445) 2016-08-10T19:04:55Z 2016-08-10T19:04:55Z 2013-07 2013-03 Article http://purl.org/eprint/type/JournalArticle 00928674 http://hdl.handle.net/1721.1/103883 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. https://orcid.org/0000-0002-0895-3557 https://orcid.org/0000-0001-8855-8647 en_US http://dx.doi.org/10.1016/j.cell.2013.06.005 Cell Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier PMC |
| spellingShingle | 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 Poised Chromatin at the ZEB1 Promoter Enables Breast Cancer Cell Plasticity and Enhances Tumorigenicity |
| title | Poised Chromatin at the ZEB1 Promoter Enables Breast Cancer Cell Plasticity and Enhances Tumorigenicity |
| title_full | Poised Chromatin at the ZEB1 Promoter Enables Breast Cancer Cell Plasticity and Enhances Tumorigenicity |
| title_fullStr | Poised Chromatin at the ZEB1 Promoter Enables Breast Cancer Cell Plasticity and Enhances Tumorigenicity |
| title_full_unstemmed | Poised Chromatin at the ZEB1 Promoter Enables Breast Cancer Cell Plasticity and Enhances Tumorigenicity |
| title_short | Poised Chromatin at the ZEB1 Promoter Enables Breast Cancer Cell Plasticity and Enhances Tumorigenicity |
| title_sort | poised chromatin at the zeb1 promoter enables breast cancer cell plasticity and enhances tumorigenicity |
| url | http://hdl.handle.net/1721.1/103883 https://orcid.org/0000-0002-0895-3557 https://orcid.org/0000-0001-8855-8647 |
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