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J. Biol. Chem., Vol. 281, Issue 19, 13047-13056, May 12, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/19/13047    most recent M513033200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kang, H. J. Articles by Bae, I. Search for Related Content PubMed PubMed Citation Articles by Kang, H. J. Articles by Bae, I. Social Bookmarking                      What's this?

BRCA1 Plays a Role in the Hypoxic Response by Regulating HIF-1 Stability and by Modulating Vascular Endothelial Growth Factor Expression^*

Hyo Jin Kang, Hee Jeong Kim, Jeong-Keun Rih, Thomas L. Mattson, Kyu Won Kim, Chi-Heum Cho^¶, Jennifer S. Isaacs^||, and Insoo Bae¹

From the Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, D. C. 20057, the Division of Pharmaceutical Bioscience, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 135-725, Republic of Korea, the ^¶Department of Obstetrics and Gynecology, Keimyung University School of Medicine, Daegu 700-712, Republic of Korea, and the ^||Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, South Carolina 29425

A recent study of breast cancer patients with and without BRCA1 gene mutations found significantly lower levels of VEGF in serum from patients with BRCA1 mutations (Tarnowski, B., Chudecka-Glaz, A., Gorski, B., and Rzepka-Gorska, I. (2004) Breast Cancer Res. Treat. 88, 287–288). Here, we describe a possible mechanistic explanation for this correlation. Because hypoxia in tumors stimulates VEGF expression and secretion we hypothesized that altered BRCA1 protein levels in breast tumors could affect hypoxia-stimulated VEGF promoter activity. This possibility was tested in cells transfected with various combinations of expression plasmids for BRCA1, BRCA1 specific inhibitory RNAs (BRCA1-siRNAs), HIF-1, and a VEGF promoter-reporter and then incubated in normoxia (21%, O₂) or hypoxia (0.1%, O₂). As predicted, increased BRCA1 levels enhanced both hypoxia-stimulated VEGF promoter activity and the amounts of VEGF mRNA, as determined by semiquantitative RT-PCR and quantitative real time PCR. Using the ChIP assay, we discovered that BRCA1 could be recruited to the endogenous human VEGF promoter along with HIF-1 following hypoxia. An interaction between BRCA1 and HIF-1 was found in human breast cancer cells. We also found that hypoxia-stimulated VEGF promoter activity and secretion was reduced in cells containing reduced amounts of endogenous BRCA1 protein (obtained by transfecting with BRCA1 siRNAs). A mechanistic explanation for these effects is provided by our finding a reduced half-life and reduced accumulation of HIF-1 in hypoxic cells transfected with BRCA1-siRNAs and that proteasome inhibitors blocked these effects of BRCA1-siRNAs. Thus, our results suggest that normal amounts of BRCA1 function in hypoxia to regulate HIF-1 stability, probably by interacting with HIF-1.

Received for publication, December 6, 2005 , and in revised form, March 8, 2006.

^* This work was supported by Grant E014440-01 (to I. B.) from the NIEHS, National Institutes of Health and by the United States Department of Defense Army Idea Award (DAMD17-02-1-0525) (to I. B.) and the American Cancer Society (IRG 97-152-13) (to I. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Rd., NW, Washington, D. C. 20057-1469. Tel.: 202-687-5267; Fax: 202-687-7256; E-mail: ib42{at}georgetown.edu.

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