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University of North Carolina Lineberger Comprehensive Cancer Center researchers published new findings that help explain one path that breast cancers can take as they leave tumors and spread throughout the body.

In the journal Nature Communications, they also reported the discovery of a biological mechanism that is key to cancer’s spread to distant sites from lymph nodes in the body. By better understanding how breast cancer spreads, they hope to be able to prevent it from happening.

UNC Lineberger’s Chad Pecot, MD.

“We have evidence that lymph node metastases resemble distant metastases more than primary tumors,” said UNC Lineberger’s Chad Pecot, MD, associate professor in the UNC School of Medicine Division of Hematology/Oncology and the senior author of the study. “This implies distant metastasis may be seeded by lymph node metastasis; a very controversial area of metastasis.”

Using genetic clues to track breast cancer’s spread

Researchers discovered evidence that breast cancer can first migrate to the lymph nodes, a filtration node for the body’s immune system, before spreading to distant sites.

They drew these conclusions from a genetic analysis of seven breast cancer cases in which samples were taken from the primary tumors, lymph node metastasis and distant sites through the UNC Rapid Autopsy Program, led by UNC Lineberger’s Lisa Carey, MD, FASCO, the Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research in the UNC School of Medicine Division of Hematology/Oncology.

They found that breast cancer samples taken from distant sites, such as in the brain or other organs, shared more genetic features with samples from the lymph nodes compared with the primary breast tumors. Five out of seven cases showed genetic similarities between distant metastases and lymph nodes.

They also tracked the spread of the breast cancer in a new laboratory model they developed and found that tumors in the lymph node were highly efficient at spreading to the brain and the lungs.

Yvonne Chao, MD, PhD.

“Most of the experimental models that people use to study metastasis in the lab focus on the idea that cancer spreads through the blood – ignoring that lymph nodes could be an important avenue through which metastasis occurs,” said the study’s co-first author Yvonne Chao, MD, PhD instructor in the UNC School of Medicine Division of Hematology/Oncology. “We are one of the first to show how lymph nodes give rise to distant metastasis.”

What genes control cancer’s spread?

To determine the biological components that are causing the spread of the tumors, they analyzed the genes that are expressed in the primary tumors and the metastatic tumors. They identified 206 genes that were differently expressed in the lymph nodes compared to the primary breast tumors and other sites.

They found that the gene HDAC11 regulates lymph node metastasis. HDAC11 is a gene that is involved in controlling how many other genes are expressed.

They studied the impact of using therapeutic drug compounds to try to block this gene. And while they found that it can decrease growth of tumors in the lymph node, they also found that it “substantially” increases migration and distant metastasis formation.

Chao said this last finding raises questions about the use of this compound by itself to prevent metastasis.

“This reveals one of the challenges of targeting metastasis,” she said. “If you shut down this process at one end, you may be promoting the other end. That is one of the inherent challenges of targeting metastasis, which is a cascade of events.”

In addition to Pecot and Chao, other authors included Patrick L. Leslie, co-first author of the paper, Yi-Hsuan Tsai, Subrata K. Ghosh, Alessandro Porrello, Amanda E.D. van Swearingen, Emily B. Harrison, Brian C. Cooley, Joel S. Parker, and Lisa Carey.

Funding: The UNC Flow Cytometry Core Facility and UNC Lineberger Animal Histopathology and Animal Studies Cores are all supported in part by the National Cancer Institute. The UNC Flow Cytometry Core Facility is also supported in part by the N.C. Biotechnology Center. The UNC Breast Cancer Rapid Autopsy Program is supported by a Susan G. Komen Scholar Award and the UNC Specialized Program of Research Excellence. Individual researchers were supported by National Cancer Institute, the National Institutes of Health, the American Cancer Society, the Jimmy V Foundation Scholar award, the UCRF Innovator Award, the Stuart Scott V Foundation/Lung Cancer Initiative Award for Clinical Research, the University Cancer Research Fund, the Lung Cancer Research Foundation, the Free to Breathe Metastasis Research Award, the Susan G. Komen Career Catalyst Award and a NCBC translational research grant.