Growth factor stimulation induces a distinct ERα cistrome underlying breast cancer endocrine resistance
- Mathieu Lupien1,2,3,8,
- Clifford A. Meyer4,8,
- Shannon T. Bailey1,2,
- Jérôme Eeckhoute5,
- Jennifer Cook1,2,
- Thomas Westerling1,2,
- Xiaoyang Zhang3,
- Jason S. Carroll6,
- Daniel R. Rhodes7,
- X. Shirley Liu2,10 and
- Myles Brown1,2,9
- 1Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;
- 2Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 3Department of Genetics, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA;
- 4Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, Massachusetts 02115, USA;
- 5UMR CNRS 6026, Université de Rennes 1, 35042 Rennes, France;
- 6Cancer Research UK, Cambridge Research Institute, Cambridge CB2 0RE, United Kingdom;
- 7Compendia Bioscience, Inc., Ann Arbor, Michigan 48104, USA
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↵8 These authors contributed equally to this work.
Abstract
Estrogen receptor α (ERα) expression in breast cancer is predictive of response to endocrine therapy; however, resistance is common in ERα-positive tumors that overexpress the growth factor receptor ERBB2. Even in the absence of estrogen, ERα can be activated by growth factors, including the epidermal growth factor (EGF). EGF induces a transcriptional program distinct from estrogen; however, the mechanism of the stimulus-specific response is unknown. Here we show that the EGF-induced ERα genomic targets, its cistromes, are distinct from those induced by estrogen in a process dependent on the transcription factor AP-1. The EGF-induced ERα cistrome specifically regulates genes found overexpressed in ERBB2-positive human breast cancers. This provides a potential molecular explanation for the endocrine therapy resistance seen in ERα-positive breast cancers that overexpress ERBB2. These results suggest a central role for ERα in hormone-refractory breast tumors dependent on growth factor pathway activation and favors the development of therapeutic strategies completely antagonizing ERα, as opposed to blocking its estrogen responsiveness alone.
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Footnotes
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↵9 Corresponding authors.
E-MAIL myles_brown{at}dfci.harvard.edu; FAX (617) 632-5417.
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↵10 E-MAIL xsliu{at}jimmy.harvard.edu; FAX (617) 632-2444.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1944810.
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Supplemental material is available at http://www.genesdev.org.
- Received September 10, 2009.
- Accepted August 16, 2010.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press