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 arise from these genetic miscues, about half of which are linked to the abnormal functioning of 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. They found that because cyclin D1 binds to the same estrogen receptor as does BRCA1, when the cell is flooded with cyclin D1, BRCA1 is unable to activate a pathway 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 vector that blocks cyclin D1 in breast tumors, you can block the growth of those tumors," said Richard Pestell, M.D., Ph.D., director of the Lombardi Comprehensive Cancer Center at Georgetown University Medical Center and senior author of the paper published in the August 1 issue of Cancer Research.
Also part of the Georgetown University research team were Chenguang Wang, Ph.D., assistant professor at the Lombardi Comprehensive Cancer Center and the lead author of the article, and Georgetown Professor of Oncology Eliot M. Rosen, a co-investigator on the study, which was funded in part by a grant from the Department of Defense. Participating in the research from the Georgetown oncology department were Saijun Fan, Zhiping Li, Maofu Fu, Mahadev Rao, Yongxian Ma, 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 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 (ERa) that is shared by both cyclin D1 and BRCA1. This research builds on a major discovery by the laboratory by Dr. Rosen, showing that BRCA1 interacts with, and inhibits the activity of ERa, 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 ERa hormone receptor."