Lipid metabolism as a driver of therapy resistance in triple-negative breast cancer

Lipid metabolism as a driver of therapy resistance in triple-negative breast cancer

Lipid metabolism has emerged as a central player in the progression and resistance to therapy of breast cancer, particularly in the aggressive subtype known as triple-negative breast cancer (TNBC). This review highlights how perturbations in lipid regulation can significantly influence the behavior of breast cancer cells and affect their growth, metastasis and response to treatment.

Changes in the metabolism of fatty acids, cholesterol, sphingolipids, and glycolipids are deeply intertwined with the survival and invasiveness of breast cancer cells. Fatty acid uptake and biosynthesis are particularly upregulated in tumor cells, which not only addresses cellular energy requirements but also supports membrane synthesis and intracellular signaling. Key enzymes and transporters such as CD36, FASN and FABP4 are instrumental in facilitating this metabolic shift, thereby improving tumor proliferation and metastatic potential.

In cholesterol metabolism, the focus is on how increased cholesterol synthesis and its potent metabolite 27-hydroxycholesterol (27HC) accelerate tumor progression and impair immune responses. Proteins such as SREBP2, NSDHL and Stard4 further contribute to this dysregulation, enhancing cancer cell survival and proliferation. The interaction of 27HC with estrogen receptors and immunomodulatory pathways complicates therapeutic strategies, particularly in hormone-sensitive and resistant tumors.

The dual nature of sphingolipid metabolism, particularly the contrasting roles of ceramide and its glycosylated derivatives, highlights a complex metabolic paradox. While ceramide accumulation exhibits tumor-suppressive effects, including increased apoptosis and chemotherapy sensitization, glycosylated forms such as Globo-H-ceramide and GD2 are associated with the maintenance of tumorigenesis, angiogenesis, and cancer stem cells.

A key outcome of lipid reprogramming is its role in promoting epithelial mesenchymal transition (EMT), a process associated with enhanced migratory ability and drug resistance. Factors such as Elovl2, SGMS2, ​​and CXCL8 modulate EMT through complicated signaling cascades including TGF-β, PI3K/AKT, and SREBP1/2 axes.

Aside from intrinsic cancer cell metabolism, the surrounding tumor immune microenvironment also adjusts (time) in response to lipid cues. M2 macrophages, cancer-associated fibroblasts, and CD8+ T cells exhibit lipid-driven phenotypic shifts that support tumor identification and treatment failure.

Resistance to standard treatments - including chemotherapy, endocrine therapy, HER2-targeted therapy and immune checkpoint inhibitors - is closely related to the rewiring of lipid metabolism. Upregulation of CD36, Fasn, CPT1, and GPR120 illustrates how tumor cells exploit lipid pathways to avoid apoptosis, reduce drug accumulation, and maintain lineage builders.

Sources: