Growth factor stimulation induces a distinct ERα cistrome underlying breast cancer endocrine resistance

Estrogen receptor alpha (ER alpha) expression in breast cancer is predictive of response to endocrine therapy; however, resistance is common in ER alpha-positive tumors that overexpress the growth factor receptor ERBB2. Even in the absence of estrogen, ER alpha 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 ER alpha genomic targets, its cistromes, are distinct from those induced by estrogen in a process dependent on the transcription factor AP-1. The EGF-induced ER alpha 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 ER alpha-positive breast cancers that overexpress ERBB2. These results suggest a central role for ER alpha in hormone-refractory breast tumors dependent on growth factor pathway activation and favors the development of therapeutic strategies completely antagonizing ER alpha, as opposed to blocking its estrogen responsiveness alone.