UVA School of Medicine

U VA Cancer Center researchers have identified a gene responsible for the spread of triple-negative breast cancer to other parts of the body — a process called metastasis — and developed a potential way to stop it. Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that accounts for 40,000 deaths in the United States annually. The majority of these deaths result from resistance to chemotherapy and subsequent aggressive metastases. So UVA researchers asked: What causes a primary tumor to become metastatic? This is an important question in cancer biology because patients with metastatic tumors have the highest death rate. UVA's Sanchita Bhatnagar, PhD, and her team found that the breast cancer oncogene TRIM37 not only causes the cancer to spread but also makes it resistant to chemotherapy. A new approach she and her colleagues have developed could possibly address both, the researchers hope. "Despite metastasis being the key reason for failure of cancer therapies, it remains poorly understood. We do not clearly understand what drives the metastatic growth in patients," says Bhatnagar, who was the first to identify TRIM37 as a breast cancer oncogene. "In general, several genes are altered during tumorigenesis. However, whether targeting the same genes will prevent metastatic transition remains to be addressed." Promising research from Bhatnagar's team shows that targeting TRIM37 prevents metastatic lesions in mouse models. Those findings form the foundation of her lab's current work exploring the role of TRIM37 in racial disparities in triple negative breast cancer. Incidence of the disease is disproportionately higher in African-American women compared with other races, with a 5-year survival rate in African-American patients of only 14% compared with 36% in non-African American women. Triple-Negative Breast Cancer Bhatnagar and UVA's Jogender Tushir- Singh, PhD, have developed a new approach to stop the effects of TRIM37, which they hope will prevent or significantly delay the spread of triple-negative breast cancer. This could also lower the disease's defenses against chemotherapy. Blocking the gene could benefit approximately 80% of triple negative breast cancer patients, the researchers estimate. Bhatnagar and Tushir-Singh's approach uses nanoparticles — microscopic balls of fat — to deliver treatment to block TRIM37. These nanoparticles are paired with specially engineered antibodies that bind to the cancerous cells but not to healthy cells. "As soon as the antibody finds the triple negative breast cancer cell, it binds to the receptor and is taken up by the cell," explained Tushir- Singh, of UVA's Department of Biochemistry and Molecular Genetics. "It is a kiss of death that selectively reduces the expression of TRIM37 in cancer cells and prevents the spread," says Bhatnagar. The approach could be used to deliver targeted treatments for many other cancers as well, the researchers report. "That would not only get the treatment where it needs to be, but we hope it will also help prevent unwanted side effects. Besides preventing metastases, it adds selectivity," Bhatnagar says. Breast Cancer Discovery Could Help Stop Disease's Deadly Spread D I S C O V E R Y 2 VIRGINIA MEDICINE "Despite metastasis being the key reason for failure of cancer therapies, it remains poorly understood. We do not clearly understand what drives the metastatic growth in patients." Sanchita Bhatnagar, PhD

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