Researchers Find BRCA1 Tumor Suppression Nullified By Cyclin D1

But now scientists have discovered that a protein called cyclin D1,grossly overproduced in about half of all cases of breast cancer, canalso disrupt BRCA1's normal role as a cancer inhibitor. They found thatbecause cyclin D1 binds to the same estrogen receptor as does BRCA1,when the cell is flooded with cyclin D1, BRCA1 is unable to activate apathway that stops cancer development.

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 vectorthat blocks cyclin D1 in breast tumors, you can block the growth ofthose tumors," said Richard Pestell, M.D., Ph.D., director of theLombardi Comprehensive Cancer Center at Georgetown University MedicalCenter and senior author of the paper published in the August 1 issueof Cancer Research.

Also part of the Georgetown University research team wereChenguang Wang, Ph.D., assistant professor at the LombardiComprehensive Cancer Center and the lead author of the article, andGeorgetown Professor of Oncology Eliot M. Rosen, a co-investigator onthe study, which was funded in part by a grant from the Department ofDefense. Participating in the research from the Georgetown oncologydepartment were Saijun Fan, Zhiping Li, Maofu Fu, Mahadev Rao, YongxianMa, and Chris Albanese.

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

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

The tumor-promoting action of various oncogenic sourcesupregulating expression of cyclin D1 converge at the common bindingsite on the estrogen receptor alpha (ERa) that is shared by both cyclinD1 and BRCA1. This research builds on a major discovery by thelaboratory by Dr. Rosen, showing that BRCA1 interacts with, andinhibits the activity of ERa, the protein that transduces the growthsignal of estrogen.

"This may help explain why the cyclin D1 gene and the BRCA1gene are important primarily in hormone responsive cancers," Pestellsaid. "The interaction occurs at the level of the ERa hormonereceptor."

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

Cyclin D1 interferes with BRCA1 function because the twoproteins both bind to the same spot on ERa, an important protein thatgoverns cell proliferation properties in both healthy and cancerouscells. In healthy cells, BRCA1 binds to ERa to restrain and controlestrogen-target genes that promote cell division. In cancer cells,however, cyclin D1 occupies the binding site on the ERa to promoteproliferation. The abundance of cyclin D1 pre-empts BRCA1 binding tothe estrogen receptor and negates the tumor suppressor role of theBRCA1 gene product.

In addition to their Georgetown research colleagues, Wang andPestell conducted their research in concert with Michael Lisanti,Department of Molecular Pharmacology, Albert Einstein College ofMedicine, Bronx, New York, N.Y.; Benita Katzenellenbogen, Departmentsof Molecular and Integrative Physiology and Cell and StructuralBiology, University of Illinois and College of Medicine, Urbana, Ill.;Peter J. Kushner, Metabolic Research Unit, University of California-SanFrancisco School of Medicine, San Francisco, Calif.; and Barbara Weber,Department of Molecular Genetics, University of Pennsylvania,Philadelphia, Pa.

A link to the article is available here: http://cancerres.aacrjournals.org/current.shtml

Georgetown University Medical Center is an internationallyrecognized academic medical center with a three-part mission ofresearch, teaching and patient care (through our partnership withMedStar Health). Our mission is carried out with a strong emphasis onpublic service and a dedication to the Catholic, Jesuit principle ofcura personalis--or "care of the whole person." The Medical Centerincludes the School of Medicine and the School of Nursing and HealthStudies, both nationally ranked, and the world renowned LombardiComprehensive Cancer Center.