Researchers investigate hereditary breast cancer to find new treatment approaches

Deborah Kelly and Zhi Sheng, assistant professors at the Virginia Tech Carilion Research Institute, recently received a grant from the Commonwealth Health Research Board to investigate hereditary breast cancer, an effort that may lead to new treatment approaches.

The board funds research intended to benefit Virginia residents.

The grant will fund a two-year project to study the mechanisms behind hereditary breast cancer related to the BRCA1 gene. This type of cancer often has a poor outcome, especially in Virginians compared with the national average.

"BRCA1-related tumors are usually triple negative, meaning they lack estrogen, progesterone, and Her2 receptors, which are effective drug targets for treating other forms of breast cancer," Kelly said. "Targeted treatments do not exist for BRCA1-related tumors, which tend to be more aggressive and difficult to manage by conventional therapies. They are also more likely to recur."

Kelly recently received a young investigator award from the Concern Foundation, which will provide funding to investigate the molecular mechanisms of oxidative damage that can increase the risk of breast cancer, especially when combined with a BRCA1 gene mutation.

In its healthy state, BRCA1 acts as a tumor suppressor. The BRCA1 protein, a product of the gene, helps coordinate the repair of damaged DNA in cells before they divide.

"Tumor-suppressing genes exist in all cells, but if one is mutated, the vital DNA protection is lost," Sheng said.

If the BRCA1 gene is mutated, it doesn't properly protect the DNA and can eventually lead to transformation of cells to the cancerous state.

About 12 percent of women in the general population will develop breast cancer sometime during their lives, according to the National Cancer Institute, but 55 percent to 65 percent of women who inherit a harmful BRCA1 mutation will develop breast cancer by age 70.

"Problems arise when the BRCA1 protein is mutated and cannot properly function with other protein complexes," Sheng said. "But until now, we haven't had the technology to directly view the structures, so we weren't able to see exactly what was going wrong."

With improved imaging techniques that Kelly's research team developed, Kelly and Sheng can now directly see nuclear protein complexes interacting with BRCA1.

"These new structural biology tools can help reveal protein interactions in a novel way," said Sheng, who has studied cancer biology without ever directly observing his research subjects at this level of detail. "Honestly, it's just cool."

Kelly and Sheng will map out the structure of BRCA1-related interactions in healthy and mutated versions of the protein and determine exactly how each operates at the molecular level.

"It's exciting," Sheng said. "This strategy of designing therapies based on the structure of the molecular process to be targeted is fairly new. Instead of simply screening for possible treatments, we're trying to create a solution to a challenge that is scientifically constrained and well defined."

This approach could be used for other cancers as well. Once Kelly and Sheng gain better insight into the molecular basis of BRCA1 mutations, researchers may have the information to develop new specific treatments for hereditary forms of BRCA1-related cancers.

"By identifying new molecular targets for BRCA1-related cancers," Kelly said, "we strive to improve the lives of women living with these mutations and to improve their treatment options long term."

Source: Virginia Tech Carilion Research Institute