Virginia Tech Carilion Research Institute scientists decode breast cancer protein
Affiliated Faculty Debora Kelly and her team from the Virginia Tech Carilion Research Institute have successfully determined the full architecture of the breast cancer susceptibility protein (BRCA1) for the first time. This three-dimensional information provides a potential pathway to restore the BRCA1 protein’s cancer-fighting abilities, even after it suffers damage.
Their results, published this week in Science Advances, suggest a new paradigm for better managing the mutated BRCA1 protein found in triple-negative breast cancer cells. Triple-negative breast cancer is aggressive, as its tumor cells typically lack target receptors that allow cancer-fighting drugs to be effective. The disease disproportionately affects younger women, and it has a higher rate of recurrence than other breast cancers.
Nearly 250,000 women were diagnosed with breast cancer in 2015 in the United States, according to the American Cancer Society, with about 15 percent of those cases diagnosed as triple-negative. Men can also have triple-negative breast cancer, but it’s far rarer, accounting for less than 1 percent of male breast cancers.
“Triple-negative breast cancer is rarely cured after treatment. It stays with the survivors, who often live with the daily fear of its return,” said Deborah Kelly, senior author on the paper and an associate professor at the Virginia Tech Carilion Research Institute (VTCRI). “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 mutations in the BRCA1 gene. The BRCA1 gene codes for the BRCA1 protein, which is found in every cell in the body. BRCA1 proteins are involved in protecting DNA material and preventing tumor growth.
But mutations in BRCA1 hinder its ability to protect cells.
“Mutated proteins are able to perform some of their duties, even though they’re partially compromised,” Kelly said. Her team previously found 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.”
In the Science Advances paper, Kelly and her team 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. The Kelly team used a high-powered electron microscope and other imaging tools to determine how the complex looks and works in three dimensions. 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. Kelly’s research team dubbed this region a self-destructive “hotspot.”
“The hotspot region on mutated BRCA1 renders the protein more vulnerable to cellular degradation,” said Kelly, who also is an associate professor of biological sciences in 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."
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?” Kelly asked. “If so, we may be able to restore the protein’s ability to fight cancer-causing processes.”
According to Kelly, if the restored protein behaves as normally as it looks, there could be a future treatment in which people 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.
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,” said Erica Ollmann Saphire, a professor of immunology and microbial science at The Scripps Research Institute. She was not involved in this study. “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.”