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BRCA1 tumor suppression nullified by cyclin D1 at the estrogen receptor


For about a decade, scientists have recognized that many cases of hereditary breast cancer result from a mutation of a specific gene called BRCA1, which, in its normal state, helps keep tumor formation in check. About five to 10 percent of breast cancer cases are linked to genetic miscues, about half of which are linked to BRCA1.

But now scientists have discovered that a protein called cyclin D1, grossly overproduced in about half of all cases of breast cancer, can also disrupt BRCA1’s normal role as a cancer inhibitor.

The results reaffirm cyclin D1 as a candidate target for molecular therapeutic control of breast tumor development.

"We’ve previously shown that if you have a gene therapy vector that blocks cyclin D1 in breast tumors induced by ErbB2 -- a common oncogene that many women have--you can block the growth of those tumors," said Richard Pestell, M.D., Ph.D., senior author of the paper published in the August 1 issue of Cancer Research and director of the Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, D.C.

This paper, Pestell said, identifies the mechanism by which cyclin D1 nullifies the tumor suppressor activity of BRCA1.

"Cyclin D1 is a collaborative oncogene and is sufficient for the induction of breast tumorogenesis in transgenic mice," he said. "This protein blocks the functional activity of the BRCA1 tumor suppressor. The science reported in this paper describes an important oncogene/tumor suppressor interaction."

The tumor-promoting action of various oncogenic sources upregulating expression of cyclin D1 converge at the common binding site on the estrogen receptor alpha (ER alpha) that is shared by both cyclin D1 and BRCA1. This research builds on a major discovery by the laboratory by Dr. Eliot M. Rosen, a professor of oncology at Georgetown University and a co-investigator on this study, showing that BRCA1 interacts with, and inhibits the activity of ER alpha, the protein that transduces the growth signal of estrogen.

"This may help explain why the cyclin D1 gene and the BRCA1 gene are important primarily in hormone responsive cancers," Pestell said. "The interaction occurs at the level of the ER alpha hormone receptor."

Cyclin D1 is a protein produced by cells and routinely functions in events that promote cell division. In cancer, cyclin D1 is regulated and abundantly overexpressed by a number of factors that promote tumor growth, such as the oncogenes ErB2, src, and ras. In more than half of human patients with breast cancer, tumor cells produce as much as eight times the amount of cyclin D than healthy breast cells.

Cyclin D1 interferes with BRCA1 function because the two proteins both bind to the same spot on ER alpha, an important protein that governs cell proliferation properties in both healthy and cancerous cells. In healthy cells, BRCA1 binds to ER alpha to restrain and control estrogen-target genes that promote cell division. In cancer cells, however, cyclin D1 occupies the binding site on the ER alpha to promote proliferation. The abundance of cyclin D1 pre-empts BRCA1 binding to the estrogen receptor and negates the tumor suppressor role of the BRCA1 gene product.

The lead author of the Cancer Research paper is Chenguang Wang, Ph.D., assistant professor at the Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine. Wang and Pestell conducted their research in concert with Saijun Fan, Zhiping Li, Maofu Fu, Mahadev Rao, Yongxian Ma, Chris Albanese, and Eliot Rosen, from the Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, D.C.; Michael Lisanti, Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, N.Y.; Benita Katzenellenbogen, Departments of Molecular and Integrative Physiology and Cell and Structural Biology, University of Illinois and College of Medicine, Urbana, Ill.; Peter J. Kushner, Metabolic Research Unit, University of California-San Francisco School of Medicine, San Francisco, Calif.; and Barbara Weber, Department of Molecular Genetics, University of Pennsylvania, Philadelphia, Pa. The research was funded, in part, by a grant to Dr. Rosen from the Department of Defense.

Russell Vanderboom, Ph.D. | EurekAlert!
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