Paul Basilio, MDLinx | September 25, 2017
A team of researchers at the Virginia Tech Carilion Research Institute (VTCRI) have identified the full architecture of the BRCA1 protein for the first time. This 3D information provides a potential pathway to restore the BRCA1 protein's cancer-fighting abilities, even after it is damaged. The results were published in Science Advances.
These new findings suggest a new paradigm for the management of BRCA1 mutations in triple-negative breast cancers. These types of aggressive cancers typically lack target receptors that allow cancer-fighting drugs to be effective.
The disease has a higher rate of recurrence than other breast cancers, and it disproportionately affects younger women.
"Triple-negative breast cancer is rarely cured after treatment,” said Deborah Kelly, PhD, senior author of the paper and an Associate Professor at VTCRI. “It stays with the survivors, who often live with the daily fear of its return. The question of recurrence is a ticking clock in the mind of breast cancer patients. As part of our research, we're hoping to slow down the clock, and eventually stop it completely."
Triple-negative breast cancer is often linked to inherited BRCA1 gene mutations. The gene codes for the BRCA1 protein, which is found in every cell in the body. The proteins are involved in protecting DNA material and preventing tumor growth. However, BRCA1 mutations can hinder its protective abilities.
"Mutated proteins are able to perform some of their duties, even though they're partially compromised," Dr. Kelly said.
Her team previously determined that the cell tags the BRCA1 protein with another signaling molecule, labeling BRCA1 to be degraded in cells.
"The cells destroy their own tumor-fighting ability, and, unfortunately, cancer develops," she explained.
In this paper, Dr. Kelly and her colleagues describe the first structural information for the full-length biological complex formed by BRCA1 and its collaborative partner, named BARD1.
The BRCA1-BARD1 complex forms a clamp-shaped structure and relays repair information to other parts of the cell. With the help of a high-powered electron microscope and other imaging tools, the researchers determined how the complex looks and works in three dimensions.
Armed with the structural information, they identified the region where the cell marks BRCA1 to be destroyed and sends the protein's repair mechanisms into a downward spiral. This region was dubbed a self-destructive "hotspot."
"The hotspot region on mutated BRCA1 renders the protein more vulnerable to cellular degradation," said Dr. Kelly, who also is an Associate Professor of Biological Sciences at Virginia Tech's College of Science. "We found that we could remove the signaling tag in the BRCA1 hotspot and make the protein look perfectly normal.”
Dr. Kelly and her team are now testing the behavior of mutated BRCA1 proteins they've restored to normal appearance.
"If the protein looks normal, does it also act normally?" Dr. Kelly asked. "If so, we may be able to restore the protein's ability to fight cancer-causing processes."
She states that if the restored protein behaves as normally as it looks, patients with this particular BRCA1 mutation could simply take a pill to prevent their cells from destroying their BRCA1 proteins in the first place.
"We know that mutations in BRCA1 are linked to aggressive forms of hereditary cancer, and that targeting the molecule with anti-cancer drugs could save lives,” said Erica Ollmann Saphire, PhD, a Professor of Immunology and Microbial Science at The Scripps Research Institute who was not involved in this study. “However, how to target the molecule and how to develop those drugs were unclear because no one has ever seen the BRCA1 structure in its entirety. By revealing the structure of this cancer-related protein for the first time, the Kelly lab and VTCRI have provided the road map to developing new anti-cancer therapeutics. This structure will also open new avenues for research to understand the mechanisms of cancer and prevention."
Elizabeth Alli, PhD, an Assistant Professor in the Department of Cancer Biology at Wake Forest University School of Medicine, said Dr. Kelly and her team employed an innovative approach to describe a structural defect in the mutated form of BRCA1 and to demonstrate that the mutant structure may be restored by enzymatic manipulation. Dr. Alli was not involved in the study.
"It's a very exciting study that highlights the importance and utility of three-dimensional structural analyses," said Dr. Alli, who studies BRCA1 and its role in DNA repair. "These data provide key information that may be further explored to better understand the tumor suppressor function of BRCA1 and to develop new strategies for the prevention or treatment of BRCA1-mutated cancers."
Dr. Kelly is now studying the function of mutant BRCA1 proteins that are restored to structural normalcy. The mutant BRCA1 protein may look healthy, but it’s not yet clear if it behaves as it should.
“We’re still years away from a preventative or restorative treatment, but our ability to see BRCA1 in three dimensions is providing new insights for rational drug design and the real possibility of bringing a precision medicine approach to this disease,” she said. “We’re beginning to understand the mechanisms of the cancer clock and how to stop the ticking.”
Michael Friedlander, PhD, the Founding Executive Director of VTCRI, spoke highly of Dr. Kelly’s contributions to both the Institute and science overall.
“We were extremely fortunate to recruit Dr. Kelly to the VTCRI from Harvard as one of the original institute research team leaders,” he said. “Debbie has met and exceeded our expectations, developing a premiere structural biology research enterprise, applying powerful molecular imaging and computational approaches to develop new insights into cancer. Her latest work on the structure of the BRCA1 protein in triple-negative breast cancer and the development of a new strategy for potentially ameliorating the structural and functional deficit is absolutely paradigm shifting.”
To read more about this study, click here.