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Estrogen Receptor- Phosphorylated at Ser¹¹⁸ Is Present at the Promoters of Estrogen-Regulated Genes and Is Not Altered Due to HER-2 Overexpression

¹ Department of Biochemistry and Medical Genetics and ² Department of Pathology, Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Manitoba, Canada

Requests for reprints: Leigh Murphy, Manitoba Institute of Cell Biology, University of Manitoba, 675 McDermot Avenue, Winnipeg, Manitoba, Canada, R3E 0V9. Phone: 204-787-4071; Fax: 204-787-2190; E-mail: lcmurph{at}cc.umanitoba.ca.

Detection of estrogen receptor (ER)- phosphorylated at Ser¹¹⁸ (P-Ser¹¹⁸-ER-) may be an indicator of an intact ligand-dependent ER- in breast tumors in vivo and may predict responsiveness to endocrine therapy. The current study addresses whether P-Ser¹¹⁸-ER- is functionally involved in ER target gene transcription and if this is modulated by HER-2 overexpression. Using chromatin immunoprecipitation analysis, P-Ser¹¹⁸-ER- was found associated with the promoters of several estrogen-regulated genes in MCF-7 breast cancer cells 30 minutes following estrogen treatment. Coactivators AIB1 and p300 were coimmunoprecipitated with P-Ser¹¹⁸-ER- following estrogen treatment. The overexpression of HER-2 protein in MCF-7 cells did not affect estrogen induction of phosphorylation of Ser¹¹⁸ or its presence at the promoters of several estrogen-regulated genes. U0126, an inhibitor of mitogen-activated protein kinase (MAPK) pathway, had no effect on P-Ser¹¹⁸-ER-. The lack of effect of HER-2 overexpression on P-Ser¹¹⁸-ER- expression in cell models is supported by similar levels of expression of P-Ser¹¹⁸-ER- in ER⁺/HER-2-overexpressing and ER⁺/HER-2^– breast tumors in vivo. Using inhibitors of cyclin-dependent kinase 7 (Cdk7), [(5,6-dichloro-1-ß-D-ribofuranosylbenzimidazole and 2-(R)-1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine], and IB kinase- (IKK-; BAY-11-7082), we show that IKK-, but not Cdk7, is at least in part involved in estrogen-mediated phosphorylation at Ser¹¹⁸ in MCF-7 cells. Our data provide direct evidence for a functional role of P-Ser¹¹⁸-ER- in estrogen-regulated signaling and do not support the hypothesis that resistance of breast tumors to tamoxifen therapy involves ligand independent activation of ER- due to constitutive phosphorylation of Ser¹¹⁸ by constitutive activation of MAPK pathway. (Cancer Res 2006; 66(20): 10162-70)

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