Fatty Acid Oxidation-Driven Src Links Mitochondrial Energy Reprogramming and Oncogenic Properties in Triple-Negative Breast Cancer

Transmitochondrial cybrids and multiple OMICs approaches were used to understand mitochondrial reprogramming and mitochondria-regulated cancer pathways in triple-negative breast cancer (TNBC). Analysis of cybrids and established breast cancer (BC) cell lines showed that metastatic TNBC maintains high levels of ATP through fatty acid β oxidation (FAO) and activates Src oncoprotein through autophosphorylation at Y419. Manipulation of FAO including the knocking down of carnitine palmitoyltransferase-1A (CPT1) and 2 (CPT2), the rate-limiting proteins of FAO, and analysis of patient-derived xenograft models confirmed the role of mitochondrial FAO in Src activation and metastasis. Analysis of TCGA and other independent BC clinical data further reaffirmed the role of mitochondrial FAO and CPT genes in Src regulation and their significance in BC metastasis. [Display omitted] •Metastatic TNBC is dependent on mitochondrial FAO energy metabolism•FAO activates c-Src via autophosphorylation at residue Y419•CPT genes are critical in TNBC tumor progression and metastasis•Reduction of fat or FAO may provide clinical benefit to TNBC patients Park et al. show that mitochondrial fatty acid β oxidation is an important energy pathway in metastatic triple-negative breast cancer. Their results uncover the significance of mitochondrial energy reprogramming in the tumor properties of triple-negative breast cancer and regulation of the Src cancer pathway by post-translational modification.