Northwestern Medicine scientists have identified a protein that plays a role in the metabolic reprogramming of some breast cancer cells, allowing them to survive when they spread to the brain, according to a study published in Oncogene.
Cancer cells migrating to and growing in the brain can be grave development for breast cancer patients, so disabling this protein may represent a novel strategy to prevent and treat breast cancer brain metastases, said Alex Cordero-Casanovas, PhD, postdoctoral fellow and lead author of the study.
Maciej “Matt” Lesniak, MD, the Michael J. Marchese Professor and chair of Neurological Surgery, was senior author of the study.
About 25 to 30 percent of breast cancer patients experience metastasis to the brain, which limits survival in those cases to an average of less than ten months, according to the study authors. The spread of breast cancer cells to the brain is correlated with the overexpression of human epidermal growth factor receptor 2 (HER2) in cancer cells, but the mechanisms driving this correlation were unknown.
Treatments such as Trastuzumab (Herceptin) can help fight HER2-positive breast cancer, but these drugs are often unable to cross the blood-brain barrier, leaving clinicians with limited options to fight brain metastases once they appear.
“This is the reason why it is crucial to understand the biological mediators and regulators of HER2-positive breast cancer metastasis and survival in the brain,” Cordero-Casanovas said.
In the current study, scientists combed through publicly available genomic databases, discovering that increased levels of the fatty acid-binding protein 7 (FABP7), a lipid-binding protein in the brain, correlated with lower survival and higher incidence of brain metastases in HER2-positive breast cancer patients. Notably, FABP7 is not found in elevated levels in the primary HER2-positive breast tumors, instead only found in tumor cells growing in the brain, according to the findings.
Next, they reduced expression of FABP7 in cell models of HER2-positive breast cancer brain metastases, finding a large decrease in the ability of the cancer to invade neighboring cells, a phenomenon that is a hallmark of cancer metastasis and the first step before cancer cells spread to other organs.
The investigators then examined the effects of targeting FABP7 on the expression of other proteins using mass spectrometry, discovering that it regulates the metabolic reprogramming of cancer cells that allows them to adapt and grow in the unique environment of the brain.
In mouse models, the investigators found that disabling FABP7 prevented HER2-positive breast cancer metastasizing into the brain.
“These results show FABP7 acts as a metabolic switch in HER2+ breast cancer cells to support their adaptation and growth in the brain microenvironment,” Cordero-Casanovas said.
According to the authors, FABP7 could be used in the future as a biomarker or therapeutic target for breast cancer patients. If high levels of FABP7 were detected in breast cancer patients, it might signal the patient is at risk for cancer spreading to their brain, and targeting or disabling FABP7 could be a promising strategy to prevent or treat breast cancer brain metastasis.
Atique Ahmed, PhD, assistant professor of Neurological Surgery, was a co-author of the study. Ahmed and Lesniak are members of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University
This work was supported by National Institutes of Health grants R35CA197725, R01NS87990, R01NS093903 (MSL), and 1R01NS096376-01A1 (AUA).
