Growth factor stimulation induces a distinct ER(alpha) cistrome underlying breast cancer endocrine resistance.
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.
Lupien
Mathieu
M
Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Meyer
Clifford A
CA
Bailey
Shannon T
ST
Eeckhoute
Jérôme
J
Cook
Jennifer
J
Westerling
Thomas
T
Zhang
Xiaoyang
X
Carroll
Jason S
JS
Rhodes
Daniel R
DR
Liu
X Shirley
XS
Brown
Myles
M
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
D004815:Epidermal Growth Factor; D047628:Estrogen Receptor alpha; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human