Growth factor stimulation induces a distinct ERα cistrome underlying breast cancer endocrine resistance
- 1 October 2010
- journal article
- Published by Cold Spring Harbor Laboratory in Genes & Development
- Vol. 24 (19), 2219-2227
- https://doi.org/10.1101/gad.1944810
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.Keywords
This publication has 68 references indexed in Scilit:
- An oestrogen-receptor-α-bound human chromatin interactomeNature, 2009
- ChIP-seq accurately predicts tissue-specific activity of enhancersNature, 2009
- Regulation of ERBB2 by oestrogen receptor–PAX2 determines response to tamoxifenNature, 2008
- FoxA1 Translates Epigenetic Signatures into Enhancer-Driven Lineage-Specific TranscriptionCell, 2008
- Genomic analysis of estrogen cascade reveals histone variant H2A.Z associated with breast cancer progressionMolecular Systems Biology, 2008
- A stromal gene signature associated with inflammatory breast cancerInternational Journal of Cancer, 2007
- The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesisOncogene, 2007
- Genomic and transcriptional aberrations linked to breast cancer pathophysiologiesCancer Cell, 2006
- Genome-wide analysis of estrogen receptor binding sitesNature Genetics, 2006
- Chromosome-Wide Mapping of Estrogen Receptor Binding Reveals Long-Range Regulation Requiring the Forkhead Protein FoxA1Cell, 2005