Growth factor stimulation induces a distinct ER(alpha) cistrome underlying breast cancer endocrine resistance.

摘要

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