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Horm Metab Res 2007; 39(3): 179-185
DOI: 10.1055/s-2007-970415
Original Basic

© Georg Thieme Verlag KG Stuttgart · New York

Insulin-like Growth Factor-I Controls BRCA1 Gene Expression through Activation of Transcription Factor Sp1

S. Maor 1 , M. Z. Papa 2 , R. I. Yarden 3 , E. Friedman 4 , Y. Lerenthal 1 , S. W. Lee 5 , D. Mayer 6 , H. Werner 1
  • 1Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
  • 2Department of Oncological Surgery, Chaim Sheba Medical Center, Tel Hashomer, Israel
  • 3Laboratory of Genomic Applications, Chaim Sheba Medical Center, Tel Hashomer, Israel
  • 4The Susanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Tel Hashomer, Israel
  • 5Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA
  • 6Group on Hormones and Signal Transduction, German Cancer Research Center, Heidelberg, Germany
Weitere Informationen

Publikationsverlauf

received 29. 6. 2006

accepted 25. 9. 2006

Publikationsdatum:
20. März 2007 (online)

Auch verfügbar auf
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Abstract

The insulin-like growth factors (IGFs) have a central role in mammary gland growth and differentiation as well as in breast cancer development. The BRCA1 gene encodes a pleiotropic protein that functions as a transcription factor. Germline BRCA1 mutations are associated with inherited predisposition to breast and ovarian cancer and confer a substantially increased risk for developing these neoplasms. Several lines of evidence led us to hypothesize that there is a functional interaction between the BRCA1 and IGF-I systems relevant to breast cancer biology. The present study tested the notion that BRCA1 gene expression is regulated by the IGF-I signaling pathway. Results of Western immunoblotting and RT-PCR analyses show that IGF-I stimulates BRCA1 protein and mRNA levels. Transient transfection experiments using BRCA1 promoter-luciferase reporter constructs reveal that IGF-I enhances BRCA1 promoter activity, suggesting that the effect of IGF-I is mediated at the transcriptional level. In addition, we provide evidence that the Sp1 zinc-finger protein is directly involved in BRCA1 gene transactivation. Combined, our data suggests that, at least part of the biological actions of IGF-I in mammary gland cells may be mediated through BRCA1. Dysregulated BRCA1 expression resulting from aberrant IGF signaling may have important consequences relevant to breast cancer pathogenesis.

Keywords

IGF-I - IGF-I receptor - BRCA1 - breast cancer - transcription - Sp1

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Correspondence

H. Werner

Department of Human Molecular Genetics and Biochemistry·Sackler School of Medicine·Tel Aviv University

Tel Aviv 69978

Israel

Telefon: +972/3/640 85 42

Fax: +972/3/640 60 87

eMail: hwerner@post.tau.ac.il

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