title: Growth factor stimulation induces a distinct ER(alpha) cistrome underlying breast cancer endocrine resistance.
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.
authors.affiliation: Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lupien
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Meyer
authors.forename: Shannon T
authors.initials: ST
authors.lastname: Bailey
authors.forename: Jérôme
authors.initials: J
authors.lastname: Eeckhoute
authors.forename: Jennifer
authors.initials: J
authors.lastname: Cook
authors.forename: Thomas
authors.initials: T
authors.lastname: Westerling
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Zhang
authors.forename: Jason S
authors.initials: JS
authors.lastname: Carroll
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Rhodes
authors.forename: X Shirley
authors.initials: XS
authors.lastname: Liu
authors.forename: Myles
authors.initials: M
authors.lastname: Brown
mesh_terms: D001943:Breast Neoplasms / Q000503:physiopathology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004815:Epidermal Growth Factor / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism
chemical_list: D004815:Epidermal Growth Factor; D047628:Estrogen Receptor alpha; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human