Breast cancer cells disguise themselves as neurons to cause brain tumors

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Breast cancer cells disguise themselves as neurons to cause brain tumors New City of Hope research explains how breast cancer becomes brain cancer years after initial diagnosis DUARTE, Calif. – Treatment and "cure" of breast cancer doesn't ensure that the disease won't spread to the brain. Too often, sometimes years after an initial diagnosis and remission, breast cancer cells are discovered growing as new tumors within the brain. Now City of Hope researchers have found how this happens.

Breast cancer cells masquerade as neurons, allowing them to hide from the immune system, cross the blood-brain barrier and begin to form ultimately-deadly brain tumors, the researchers found.

"The most dreaded location for cancer to spread is the brain," said Rahul Jandial, M.D., Ph.D.,a City of Hope neurosurgeon who led the study, available online and slated for print publication in the Proceedings of the National Academy of Science in February. "As we have become better at keeping cancer at bay with drugs such as Herceptin, women are fortunately living longer. In this hard-fought life extension, brain metastases are being unmasked as the next battleground for extending the lives of women with breast cancer."

Jandial and other City of Hope scientists wanted to explore how breast cancer cells cross the blood-brain barrier – a separation of the blood circulating in the body from fluid in the brain – without being destroyed by the immune system.

"If, by chance, a malignant breast cancer cell swimming in the bloodstream crossed into the brain, how would it survive in a completely new, foreign habitat?"Jandial said. Jandial and his team's hypothesis: Given that the brain is rich in many brain-specific types of chemicals and proteins, perhaps breast cancer cells exploit these resources by assuming similar properties. These cancer cells could potentially deceive the immune system by blending in with the neurons, neurotransmitters, other types of proteins, cells and chemicals.

Taking samples from brain tumors resulting from breast cancer, Jandial and his team found that the breast cancer cells were using the brain's most abundant chemical as a fuel source. This chemical, GABA, is a neurotransmitter used for communication between neurons.

When compared to cells from non-metastatic breast cancer, the metastasized cells expressed a receptor for GABA, as well as for a protein that draws the transmitter into cells. This allowed the cancer cells to essentially masquerade as neurons.

"Breast cancer cells can be cellular chameleons (or masquerade as neurons) and spread to the brain," Jandial said.

Jandial says that further study is required to better understand the mechanisms that allow the cancer cells to achieve this disguise. He hopes that ultimately, unmasking these disguised invaders will result in new therapies.

### The research was completed in partnership with John Termini, Ph.D., and Eugene Roberts, Ph.D, director emeritus of Neurobiochemistry at City of Hope. Other City of Hope researchers on the study were Josh Neman, Ph.D.; Sharon Wilczynski, M.D., Ph.D.; Nagarajan Vaidehi, Ph.D.; Cecilia Choy, Claudia M. Kowolik, Ph.D.; Huber Li; and Amanda C. Hambrecht of University of Southern California.

This study is supported by National Institutes of Health grants 2K12CA001727-16A1, R01CA176611-01, R01-GM082896 and R01-GM097261, plus National Cancer Institute grant P30-CA033572.