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Brain metastasis (BrM) is a key contributor to morbidity and mortality in breast cancer patients, especially among high-risk epidermal growth factor receptor 2-positive (HER2+) and triple-negative/basal-like molecular subtypes. Optimal management of BrM is focused on characterizing a ‘BrM dependency map’ to prioritize targetable therapeutic vulnerabilities. We review recent studies addressing the targeting of BrM in the lipid-deprived brain environment, which selects for brain-tropic breast cancer cells capable of cell-autonomously generating fatty acids by upregulating  de novo  lipogenesis  via  fatty acid synthase (FASN). Disruption of FASN activity impairs breast cancer growth in the brain, but not extracranially, and mapping of the molecular causes of organ-specific patterns of metastasis has uncovered an enrichment of lipid metabolism signatures in brain metastasizing cells. Targeting  SREBP1 –the master regulator of lipogenic gene transcription–curtails the ability of breast cancer cells to survive in the brain microenvironment. Targeting FASN represents a new therapeutic opportunity for patients with breast cancer and BrM. Delivery of brain-permeable FASN inhibitors and identifying strategies to target metabolic plasticity that might compensate for impaired brain FASN activity are two potential roadblocks that may hinder FASN-centered strategies against BrM.

Fatty acid synthase: a druggable driver of breast cancer brain metastasis