Growth Factor Stimulation Induces a Distinct ERα Cistrome Underlying Breast Cancer Endocrine Resistance

Estrogen receptor alpha (ERα) expression in breast cancer is predictive of response to endocrine therapy, however resistance is common in ERα-positive tumors that over-express 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 cistrome, 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 over-expressed in ERBB2-positive human breast cancers. This provides a potential molecular explanation for the endocrine therapy resistance seen in ERα-positive breast cancers that over-express 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. ChIP-Chip against ERa in MCF7 breast cancer cells treated with Epidermal Growth Factor (EGF) for 90 min and expression profile analysis (mRNA) in MCF7 cells treated with EGF (3h or 12h) or pre-treated with ICI182,780 and then with EGF from 3h.