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Epidermal Growth Factor–Induced Signaling in Breast Cancer Cells Results in Selective Target Gene Activation by Orphan Nuclear Receptor Estrogen-Related Receptor

¹ Molecular Oncology Group, McGill University Health Centre and ² Departments of Biochemistry, Medicine, and Oncology, McGill University, Montreal, Quebec, Canada

Requests for reprints: Vincent Giguère, Molecular Oncology Group, McGill University Health Centre, Room H5-21, 687 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1. Phone: 514-843-1406; Fax: 514-843-1478; E-mail: vincent.giguere{at}mcgill.ca.

The orphan nuclear hormone receptor estrogen-related receptor (ERR, NR3B1) is a constitutive transcription factor that is structurally and functionally related to the classic estrogen receptors. ERR can recognize both the estrogen response element and its own binding site (ERRE) in either dimeric or monomeric forms. ERR is also a phosphoprotein whose expression in human breast tumors correlates with that of the receptor tyrosine kinase ErbB2, suggesting that its transcriptional activity could be regulated by signaling cascades. Here, we investigated growth factor regulation of ERR function and found that it is phosphorylated in MCF-7 breast cancer cells in response to epidermal growth factor (EGF), an event that enhances its DNA binding. Interestingly, treatment with alkaline phosphatase shifts ERR from a dimeric to a monomeric DNA-binding factor, and only the dimeric form interacts with the coactivator PGC-1. In vitro, the DNA-binding domain of ERR is selectively phosphorylated by protein kinase C (PKC), which increases its DNA-binding activity, whereas expression of constitutively active PKC enhances TFF1 promoter activity via the ERRE. However, whereas treatment of MCF-7 cells with the phorbol ester phorbol-12-myristate 13-acetate also enhances ERR activation of the TFF1 promoter reporter, it does not affect ERR activity on its own promoter. In agreement, chromatin immunoprecipitation analysis shows that ERR and RNA polymerase II are preferentially recruited to the TFF1 promoter after EGF treatment, whereas recruitment of these factors to its own promoter is not affected. These results reveal a mechanism through which growth factor signaling can selectively activate ERR target genes in breast cancer cells.

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