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Signaling and Regulation

Estrogen-Related Receptor 1 Transcriptional Activities Are Regulated in Part via the ErbB2/HER2 Signaling Pathway

¹ McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin and ² Fox Chase Cancer Center, Philadelphia, Pennsylvania

Requests for reprints: Janet E. Mertz, McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, 1400 University Avenue, Madison, WI 53706. Phone: 608-262-2383; Fax: 608-262-2824. E-mail: mertz{at}oncology.wisc.edu

We previously showed that (a) estrogen-related receptor 1 (ERR1) down-modulates estrogen receptor (ER)–stimulated transcription in low ErbB2–expressing MCF-7 mammary carcinoma cells, and (b) ERR and ErbB2 mRNA levels positively correlate in clinical breast tumors. We show here that ERR1 represses ER-mediated activation in MCF-7 cells because it failed to recruit the coactivator glucocorticoid receptor interacting protein 1 (GRIP1) when bound to an estrogen response element. In contrast, ERR1 activated estrogen response element– and ERR response element–mediated transcription in ER-positive, high ErbB2–expressing BT-474 mammary carcinoma cells, activation that was enhanced by overexpression of GRIP1. Likewise, regulation of the endogenous genes pS2, progesterone receptor, and ErbB2 by ERR1 reflected the cell type–specific differences observed with our reporter plasmids. Importantly, overexpression of activated ErbB2 in MCF-7 cells led to transcriptional activation, rather than repression, by ERR1. Two-dimensional PAGE of radiophosphate-labeled ERR1 indicated that it was hyperphosphorylated in BT-474 relative to MCF-7 cells; incubation of these cells with anti-ErbB2 antibody led to reduction in the extent of ERR1 phosphorylation. Additionally, mitogen-activated protein kinases (MAPK) and Akts, components of the ErbB2 pathway, phosphorylated ERR1 in vitro. ERR1-activated transcription in BT-474 cells was inhibited by disruption of ErbB2/epidermal growth factor receptor signaling with trastuzumab or gefitinib or inactivation of downstream components of this signaling, MAPK kinase/MAPK, and phosphatidylinositol-3-OH kinase/Akt, with U0126 or LY294002, respectively. Thus, ERR1 activities are regulated, in part, via ErbB2 signaling, with ERR1 likely positively feedback-regulating ErbB2 expression. Taken together, we conclude that ERR1 phosphorylation status shows potential as a biomarker of clinical course and antihormonal- and ErbB2-based treatment options, with ERR1 serving as a novel target for drug development. (Mol Cancer Res 2007;5(1):71–86)

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