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pubmed:abstractText |
Estrogen receptor ? (ER?) expression in breast cancer is predictive of response to endocrine therapy; however, resistance is common in ER?-positive tumors that overexpress the growth factor receptor ERBB2. Even in the absence of estrogen, ER? 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? 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? 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?-positive breast cancers that overexpress ERBB2. These results suggest a central role for ER? in hormone-refractory breast tumors dependent on growth factor pathway activation and favors the development of therapeutic strategies completely antagonizing ER?, as opposed to blocking its estrogen responsiveness alone.
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