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More than 20 years after scientists revealed that mutations in the BRCA1 gene predispose women to breast cancer, researchers have pinpointed the molecular mechanism that allows those mutations to wreak havoc.
The findings, reported Oct. 4 in the journal Nature, should not only help researchers design drugs to combat breast and ovarian cancers, but will also help identify women who are at high risk of developing them. Colorado State University’s Claudia Wiese and David Maranon are co-authors on the study. The lead research institutions are Yale University School of Medicine and Columbia University.
Wiese, an assistant professor in the Department of Environmental and Radiological Health Sciences, said through their work, the research team learned more about the tumor-suppressing protein BARD1, and its specific function and connection with the BRCA1 gene.
“What we learned can help us understand which mutations in BARD1 are associated with an elevated cancer risk,” she said. “We haven’t discovered all the mutations that lead to cancer. But the region in BARD1 that we analyzed may be particularly important.”
Researchers know little about BARD1. Between 20 and 25 percent of familial breast cancer cases are associated with genetic mutations in BRCA1 or BRCA2. The remaining hereditary breast cancer cases are linked to mutations in other genes, including BARD1. However, recent evidence also suggests that mutations in BARD1 may be linked to breast and ovarian cancer more frequently than originally thought.
BRCA1 is involved in many different cellular processes, including a DNA repair pathway known as homologous recombination. This process repairs harmful breaks that occur on strands of DNA, said Wiese. “If you don’t have the necessary proteins, these breaks don’t get repaired correctly and you generate mutations, which then promote cancer development in patients,” she said.
Based on previous research, the scientists knew that the BRCA1-BARD1 interaction — known as a dimer, when two proteins come together — was important. But what they learned in this study was the importance of the BRCA1-BARD1 dimer in later stages of homologous recombination.
Patrick Sung, professor of molecular biophysics and biochemistry at Yale University and senior author of the study, said that while there have been about 14,000 papers written about BRCA1, “you would think we already know everything about the gene but we don’t.”
Maranon, an expert in immunofluorescence and microscopy, analyzes DNA repair structures in human cells. He said the research team will continue to study the BRCA1-BARD1 relationship.
“The team may explore the effect certain drugs might have in producing these mutations, and how to attack the mutations,” he said. “What’s still needed is some medication or therapeutic to kill cancer cells more efficiently.”
Weixing Zhao, an associate research scientist at Yale, is the co-senior author of the study, which was primarily funded by the National Institutes of Health. Additional collaborators include Yale researchers Gary Kupfer and Ryan Jensen, and Yong Xiong and Eric Greene of Columbia University.