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Sharon Maor Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
Group on Hormones and Signal Transduction, German Cancer Research Center, Heidelberg D-69120, Germany
Laboratory of Genomic Applications, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA
Department of Oncological Surgery, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel

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Doris Mayer Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
Group on Hormones and Signal Transduction, German Cancer Research Center, Heidelberg D-69120, Germany
Laboratory of Genomic Applications, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA
Department of Oncological Surgery, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel

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Ronit I Yarden Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
Group on Hormones and Signal Transduction, German Cancer Research Center, Heidelberg D-69120, Germany
Laboratory of Genomic Applications, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA
Department of Oncological Surgery, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel

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Adrian V Lee Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
Group on Hormones and Signal Transduction, German Cancer Research Center, Heidelberg D-69120, Germany
Laboratory of Genomic Applications, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA
Department of Oncological Surgery, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel

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Rive Sarfstein Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
Group on Hormones and Signal Transduction, German Cancer Research Center, Heidelberg D-69120, Germany
Laboratory of Genomic Applications, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA
Department of Oncological Surgery, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel

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Haim Werner Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
Group on Hormones and Signal Transduction, German Cancer Research Center, Heidelberg D-69120, Germany
Laboratory of Genomic Applications, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA
Department of Oncological Surgery, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel

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Moshe Z Papa Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
Group on Hormones and Signal Transduction, German Cancer Research Center, Heidelberg D-69120, Germany
Laboratory of Genomic Applications, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA
Department of Oncological Surgery, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel

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The insulin-like growth factors, IGF-I and IGF-II are a familyof mitogenic polypeptides with important roles in growth and differentiation. The biological actions of the IGFs are mediated by the IGF-I receptor (IGF-IR), a cell-surface tyrosine kinase, whose activation by serum IGF-I seems to be a key step in breast cancer initiation. Evidence accumulated indicates that estrogens stimulate the expression and activity of IGF axis components. The aim of our study was to examine the transcriptional mechanisms involved in regulation of IGF-IR gene expression by the estrogen receptor (ER). For this purpose, transient transfections using an IGF-IR promoter-luciferase reporter plasmid were performed in breast cancer-c derived ER-positive MCF-7 cells and isogenic ER-negative C4 cells. To examine the potential involvement of zinc-finger nuclear proteins in the transactivating effect of estrogens, chromatin immunoprecipitation (ChIP) experiments were performed using an Sp1 antibody, along with the Sp1-family-binding inhibitor Mithramycin A. The results obtained indicate that basal IGF-IR promoter activity was 5.8-fold higher in MCF-7 than in C4 cells. Estradiol treatment significantly activated the IGF-IR promoter in MCF-7, but not in C4 cells. Furthermore, the estrogen responsive region in the IGF-IR promoter was mapped to a GC-rich sequence located between nucleotides −40 and −188 in the 5′ flanking region. ChIP experiments revealed that at least part of the estrogen effect on IGF-IR expression was mediated through activation of the Sp1 transcription factor. In summary, our studies demonstrate that IGF-IR gene transcription in breast cancer cells is controlled by interactions between ERα and Sp1. Dysregulated expression of the IGF-IR gene may have pathologic consequences with relevance in breast cancer etiology.

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