The National Cancer Institute of the National Institutes of Health has awarded Deborah Kelly, an associate professor at the Virginia Tech Carilion Research Institute, $2 million to study the mutated form of the breast cancer susceptibility protein (BRCA1) that is implicated in hereditary breast cancer.
This is Kelly’s second five-year grant from the National Cancer Institute; the first was awarded in 2015. With both grants, she’s working to understand the molecular mechanisms underlying triple-negative breast cancer. This hard-to-treat cancer is often caused by mutations in the BRCA1 protein.
“BRCA1 normally acts as a tumor suppressor by coordinating DNA repair,” Kelly said. “With certain mutations, though, BRCA1 loses the ability to repair DNA with high fidelity. These events lead to genomic instability and provide a tipping point towards cancer induction.”
According to the Triple Negative Breast Cancer Foundation, this type of cancer can be particularly aggressive and is more likely to recur after treatment than other types of breast cancer.
Kelly uses cryo-electron microscopy to image the structure of BRCA1 proteins under near-native conditions. Kelly and her team found that the BRCA1 protein forms a C shape, with molecular complexes on either open end. In health, the protein is relatively smooth from end to end. The mutation that can lead to triple-negative breast cancer manifests as a deformation on the curve of the protein. Kelly and her team found that a chemical treatment removed the deformation, but they’re still working to understand if the restored protein can operate normally in cells.
“With the support of the first grant, we became the first team to visualize the structure of the BRCA1 protein — in health and in cancer,” said Kelly, who is also an associate professor of biology in Virginia Tech’s College of Science. “We then determined a structural difference in a ‘hotspot’ region of the mutated protein. Its constitution was very different from the healthy protein. Importantly, we were able to rescue the structure of the mutated protein so that it appeared healthy.”
To remove the deformation in the mutated BRCA1 proteins, Kelly and her team treated it with enzymes known as deubiquitinases. These enzymes effectively fixed the deformation in the hotspot area of BRCA1 and left the protein looking healthy again.
“The question that remained was whether the hotspot removal actually restored the function of the mutated protein,” Kelly said. “Our preliminary results are pointing to yes, and this grant will allow us to continue investigating this scenario as a potential therapeutic treatment.”
“The awarding of this second National Cancer Institute multimillion dollar R01 research grant from NIH to Dr. Kelly is indicative of the high esteem in which the breast cancer research community holds her and her work,” said Michael Friedlander, executive director of the VTCRI and Virginia Tech’s vice president for health sciences and technology. “Dr. Kelly is writing a whole new chapter in the science of cancer therapeutics, particularly for breast cancer, by taking a structural oncology approach to repair defective protein function. We are very fortunate to have such a visionary innovator as Dr. Kelly at the VTCRI, leading the way to new horizons in health.”
Elizabeth Ali, an assistant professor of cancer biology at the Wake Forest School of Medicine, will contribute to this project as well. Other collaborators include Virginia Tech Carilion Research Institute scientists Zhi Sheng, an assistant professor; Rob Gourdie, a professor and director of the VTCRI Center for Heart and Regeneration Medicine; and Mark Yeager, the Andrew P. Somlyo Distinguished Professor of Molecular Physiology and Biological Physics and director of the High-Resolution Cryo-EM Imaging Facility at the University of Virginia School of Medicine.