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Direct interaction between BRCA1 and the estrogen receptor regulates vascular endothelial growth factor (VEGF) transcription and secretion in breast cancer cells

Oncogene volume 21, pages 7730–7739 (2002)Cite this article

Abstract

Mutational inactivation of BRCA1 confers increased risk for breast cancer. However, the underlying basis for the breast tissue-restricted, tumor-suppressive properties of BRCA1 remains poorly defined. Here, we show that BRCA1 and the estrogen receptor α (ER-α) modulated vascular endothelial growth factor (VEGF) gene transcription and secretion in breast cancer cells. ER-α interacted in vitro and in vivo with BRCA1, and this interaction was mediated by the AF-2 domain of ER-α and two domains of BRCA1, the amino-acid residues 1–306 and 428–683. Endogenous interaction of ER-α with BRCA1 was observed in normal MCF-10A breast epithelial cells and in breast cancer cells (MCF-7 and T47D), and this interaction was significantly reduced in the presence of estrogen. Furthermore, ER-α induced activation of VEGF gene transcription, using human VEGF promoter-luciferase reporter constructs. The AF-2 domain of ER-α was also shown to induce VEGF gene transcription activation similar to that obtained with the full-length ER-α. However, in the presence of BRCA1, VEGF gene transcription activation and VEGF protein secretion were significantly inhibited in a dose-dependent manner. The BRCA1 domain of 1–683 amino acid residues was required for this inhibition of VEGF gene transcription activation. Three mutated forms of BRCA1 (A1708E, M1775R and Y1853X), that have been identified in familial breast cancers, failed to associate with ER-α and to suppress VEGF promoter activity and VEGF protein secretion. Overexpression of wild-type BRCA1 in HCC-1937 breast cancer cells that lack endogenous functional BRCA1 significantly reduced VEGF secretion in these cells. These results demonstrate a novel pathogenic mechanism whereby mutations in BRCA1, via their interaction with ER-α, could promote tumorigenesis through the hormonal regulation of mammary epithelial cell proliferation and impaired VEGF function, which may lead to cancer growth and angiogenesis.

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Acknowledgements

We are very grateful to Dr Muramatsu for providing ER-α constructs; Dr Taylor for providing VEGF-luc constructs; Mikyung Kim-Park for typing the manuscript; Dan Kelley for help with preparation of the figures; and Janet Delahanty for editing the manuscript. This work was supported in part by National Institutes of Health Grants, CA76226 (H Avraham), R21CA87290 (H Avraham), Department of Army grants DAMD17-98-1-8032 (H Avraham) and DAMD17-99-1-9078 (H Avraham), the Experienced Breast Cancer Research Grant 3480057089, Massachusetts Department of Public Health Grant, Claudia Sargent Memorial Breast Cancer Fellowship (for H Li) and Diana Michelis Fellowship in breast cancer (H Kawai). This work was done during the term of an established investigatorship from the American Heart Association (H Avraham).

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  1. Hideki Kawai and Huchun Li: Hideki Kawai and Huchun Li contributed equally to this work.

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  1. Division of Experimental Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 4 Blackfan Circle, Boston, 02115, Massachusetts, MA, USA

    Hideki Kawai, Huchun Li, Philip Chun, Shalom Avraham & Hava Karsenty Avraham

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  1. Hideki Kawai
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Correspondence to Hava Karsenty Avraham.

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Kawai, H., Li, H., Chun, P. et al. Direct interaction between BRCA1 and the estrogen receptor regulates vascular endothelial growth factor (VEGF) transcription and secretion in breast cancer cells. Oncogene 21, 7730–7739 (2002). https://doi.org/10.1038/sj.onc.1205971

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