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[Cancer Research 65, 6557-6567, August 1, 2005]
© 2005 American Association for Cancer Research

Molecular Biology, Pathobiology and Genetics

Cyclin D1 Antagonizes BRCA1 Repression of Estrogen Receptor {alpha} Activity

Chenguang Wang1, Saijun Fan1, Zhiping Li1, Maofu Fu1, Mahadev Rao1, Yongxian Ma1, Michael P. Lisanti2, Chris Albanese1, Benita S. Katzenellenbogen3, Peter J. Kushner4, Barbara Weber5, Eliot M. Rosen1 and Richard G. Pestell1

1 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, District of Columbia; 2 Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York; 3 Departments of Molecular and Integrative Physiology and Cell and Structural Biology, University of Illinois and College of Medicine, Urbana, Illinois; 4 Metabolic Research Unit, University of California-San Francisco School of Medicine, San Francisco, California; and 5 Department of Molecular Genetics, University of Pennsylvania, Philadelphia, Pennsylvania

Requests for reprints: Richard G. Pestell, Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Research Building, Room E501, 3970 Reservoir Road Northwest, Box 571468, Washington, DC 20007. Phone: 202-687-2110; Fax: 202-687-6402; E-mail: pestell{at}georgetown.edu.

The cyclin D1 gene is frequently overexpressed in human breast cancer and is capable of inducing mammary tumorigenesis when overexpressed in transgenic mice. The BRCA1 breast tumor susceptibility gene product inhibits breast cancer cellular growth and the activity of several transcription factors. Herein, cyclin D1 antagonized BRCA1-mediated repression of estrogen receptor {alpha} (ER{alpha})–dependent gene expression. Cyclin D1 repression of BRCA1 function was mediated independently of its cyclin-dependent kinase, retinoblastoma protein, or p160 (SRC-1) functions in human breast and prostate cancer cells. In vitro, cyclin D1 competed with BRCA1 for ER{alpha} binding. Cyclin D1 and BRCA1 were both capable of binding ER{alpha} in a common region of the ER{alpha} hinge domain. A novel domain of cyclin D1, predicted to form a helix-loop-helix structure, was required for binding to ER{alpha} and for rescue of BRCA1-mediated ER{alpha} transcriptional repression. In chromatin immunoprecipitation assays, 17ß-estradiol (E2) enhanced ER{alpha} and cyclin D1 recruitment to an estrogen response element (ERE). Cyclin D1 expression enhanced ER{alpha} recruitment to an ERE. E2 reduced BRCA1 recruitment and BRCA1 expression inhibited E2-induced ER{alpha} recruitment at 12 hours. Cyclin D1 expression antagonized BRCA1 inhibition of ER{alpha} recruitment to an ERE, providing a mechanism by which cyclin D1 antagonizes BRCA1 function at an ERE. As cyclin D1 abundance is regulated by oncogenic and mitogenic signals, the antagonism of the BRCA1-mediated ER{alpha} repression by cyclin D1 may contribute to the selective induction of BRCA1-regulated target genes.




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Copyright © 2005 by the American Association for Cancer Research.