Palmitic acid fuels triple-negative breast cancer through metadherin-dependent fatty acid β-oxidation: Relevance to high fat diet-induced breast cancer progression.

Diets rich in saturated fats, specifically palmitic acid (PA), are associated with increased breast cancer risk. However, the exact mechanisms linking dietary fat and cancer progression remain unclear. Herein, we show that PA increases the levels of metadherin (MTDH), an oncogene, and its spliced isoform MTDHΔ7 in triple-negative breast cancer (TNBC) cells. PA significantly increased TNBC cell proliferation and invasiveness in an MTDH-Wt/Δ7-dependent way. Intriguingly, while PA alone promoted mitochondrial fatty acid β-oxidation (FAO), the addition of PA to TNBC cells stably expressing MTDH-Wt/MTDHΔ7 further potentiated FAO and ATP production. Conversely, PA failed to increase FAO in TNBC cells stably depleted of MTDH-Wt/MTDHΔ7. Also, etomoxir, a carnitine palmitoyl transferase (CPT)1 inhibitor, decreased PA- and MTDH-Wt/Δ7-induced TNBC cell invasive potential. Mechanistically, MTDH-Wt/MTDHΔ7-mediated increase in SIRT3 activity led to the activation of CPT1 via its deacetylation, promoting FAO and raising acetyl-CoA levels. Moreover, overexpression of MTDH-Wt/MTDHΔ7 notably increased free fatty acids uptake and subsequent consumption by boosting CD36 levels. Accordingly, depletion of either SIRT3 or CD36 significantly abrogated MTDH-Wt/MTDHΔ7-induced fatty acids uptake and subsequent FAO. Thus, MTDH-Wt/MTDHΔ7 plays a crucial role in utilizing fatty acids to fuel mitochondrial metabolism in TNBC cells. Further, SCID mice bearing sh.MTDH-Wt or sh.MTDHΔ7-MDA-MB-231cells fed a high-fat diet (HFD) showed significant resistance to tumor growth and metastatic spread compared to mice bearing parental MDA-MB-231 cells fed either HFD or chow diet. In conclusion, this study highlights a novel mechanism by which PA or HFD can promote TNBC aggressiveness through MTDH-mediated upregulation of mitochondrial FAO.