Dr. Mark Glover

New discovery reveals how defects in protein cause breast cancer

Basic science work gives clinicians and patients more information upon which to make treatment decisions

Researchers at the University of Alberta have discovered a critical sequence of biochemical events that helps explain what goes wrong with DNA – the building code for life – when women get hereditary breast cancer.

For about 10 years, researchers have known that women who carry mutations in the gene BRCA1 are at high risk to develop early-onset breast and ovarian cancers. In fact, mutations in BRCA1 cause about half of all hereditary breast cancers, and therefore, have been the focus of intense study.

Although the researchers say it isn’t the whole story, they’re excited that their new findings may explain why a large number of the BRCA1 mutations cause cancers. The research, published on-line last week in Nature Structural and Molecular Biology, focuses on the BRCA1 protein, and its interactions with one of its partner proteins, BACH1. In normal cells, BRCA1 and BACH1 interact to control how damage to DNA is repaired. The group’s structural studies reveal how these proteins recognize each other, and moreover, they show why mutated forms of BRCA1 that have been isolated from breast and ovarian cancer patients, do not.

Principal researcher Mark Glover, a biochemist at the U of A explains: "Both BRCA1 and BACH1 have been shown to regulate how cells respond to DNA damage, and this response is thought to be crucial to BRCA1’s tumor-suppressor activity.

"Our work shows for the first time in three-dimensional detail how BRCA1 and BACH1 interact," says Dr. Glover. "Moreover, we have created a large set of BRCA1 protein mutants that correspond to those that have been isolated from women at risk for breast and ovarian cancer in genetic screening programs. The fact that the cancer-causing mutations block the ability of BRCA1 to interact with BACH1 really suggests that this interaction is key to how BRCA1 functions."

The paper is entitled "Structural basis of phosphopeptide recognition by the BRCT domain of BRCA1." Other authors credited include: Postdoctoral fellow Scott Williams and graduate students Megan Lee and D Duong Hau. A group from the Massachusetts Institute of Technology has also published a piece on the topic in the same issue of the journal, reflecting the intense competition among researchers around the world to understand the biochemical sequence of events. The print version of the journal is devoting its cover to an image illustrating the Glover lab’s research.

Dr. Glover first became prominent in the field in 2001, when he and his team recreated the first three dimensional structure of a critical portion of the BRCA1 protein. That work started a flood on inquiries from around the world because of its implications for designing screening programs for breast cancer. "This information can be used to help identify high-risk patients sooner and detect the disease much earlier," says Dr. Glover.

Dr. Glover’s work is funded by the Canadian Institutes of Health Research, the Alberta Heritage Foundation for Medical Research, the Canadian Cancer Society and the Canadian Breast Cancer Research Alliance.

For further information, please contact Dr. Mark Glover using the Email contact form or by phone at 780 492-2136