Breast Cancer Brain Metastases Rely on FASN-Mediated Lipid Biosynthesis

Although metastases of HER2⁺ breast cancers are sometimes treatable, brain metastases tend to be treatment-refractory. Because the brain microenvironment has been demonstrated to be deficient in several nutrients required by cancer cells, Ferraro, Ali, Luengo, and colleagues investigated metabolic differences between HER2⁺ breast tumors growing in the brains and mammary fat pads of mice. This analysis revealed that the tumors growing in the brains exhibited higher expression of genes involved in fatty acid synthesis, a finding confirmed at the protein level, and had greater metabolism of glucose to produce fatty acids. Ex vivo experiments using organotypic slice cultures confirmed that metastases grown in the brain retained increased expression of lipid synthesis genes, whereas in vitro experiments revealed that there was no such increase in brain-metastatic cells removed from brain tissue; together, these experiments suggested that the brain microenvironment itself promoted increased tumor fatty acid synthesis. Notably, fatty acid synthase (FASN) and the mRNA encoding this enzyme were more highly expressed in breast tumors that had metastasized to the brain compared with primary breast tumors or tumors that had metastasized to other sites. Further analysis showed that, in the brain, extracellular fatty acids were available to breast cancer cells only in limited quantities, explaining the need for increased lipid biosynthesis. Experiments employing FASN knockout or pharmacologic FASN inhibition revealed that FASN played a critical role in fulfilling the need for lipids in breast tumors grown in the brain, but not the liver, further supporting the notion that lipid-limiting conditions in the brain must be circumvented for breast cancer cells to establish brain metastases. Importantly, treatment with a FASN inhibitor reduced the growth of breast cancer brain metastases but not tumors in the mammary fat pad. This work supports the notion that cancer cell lipid biosynthesis is key for breast cancer brain metastasis and suggests that FASN inhibition may be a strategy of interest in controlling this condition.

Ferraro GB, Ali A, Luengo A, Kodack DP, Deik A, Abbott KL, et al. Fatty acid synthesis is required for breast cancer brain metastasis. Nat Cancer 2021;2:414–28.

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