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• W2140794979 abstract "Abstract We previously showed that (a) estrogen-related receptor α1 (ERRα1) down-modulates estrogen receptor (ER)–stimulated transcription in low ErbB2–expressing MCF-7 mammary carcinoma cells, and (b) ERRα and ErbB2 mRNA levels positively correlate in clinical breast tumors. We show here that ERRα1 represses ERα-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, ERRα1 activated estrogen response element– and ERR response element–mediated transcription in ERα-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 ERRα1 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 ERRα1. Two-dimensional PAGE of radiophosphate-labeled ERRα1 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 ERRα1 phosphorylation. Additionally, mitogen-activated protein kinases (MAPK) and Akts, components of the ErbB2 pathway, phosphorylated ERRα1 in vitro. ERRα1-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, ERRα1 activities are regulated, in part, via ErbB2 signaling, with ERRα1 likely positively feedback-regulating ErbB2 expression. Taken together, we conclude that ERRα1 phosphorylation status shows potential as a biomarker of clinical course and antihormonal- and ErbB2-based treatment options, with ERRα1 serving as a novel target for drug development. (Mol Cancer Res 2007;5(1):71–86)" @default.
• W2140794979 created "2016-06-24" @default.
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• W2140794979 date "2007-01-01" @default.
• W2140794979 modified "2023-09-27" @default.
• W2140794979 title "Estrogen-Related Receptor α1 Transcriptional Activities Are Regulated in Part via the ErbB2/HER2 Signaling Pathway" @default.
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• W2140794979 doi "https://doi.org/10.1158/1541-7786.mcr-06-0227" @default.
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