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

Cell Rep. 2016 Mar 8;14(9):2154-2165. doi: 10.1016/j.celrep.2016.02.004. Epub 2016 Feb 25.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Carcinogenesis
  • Cell Line, Tumor
  • Energy Metabolism*
  • Fatty Acids / metabolism*
  • Female
  • Humans
  • Mice, SCID
  • Mitochondria / metabolism*
  • Neoplasm Transplantation
  • Oxidation-Reduction
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Triple Negative Breast Neoplasms / metabolism*
  • Triple Negative Breast Neoplasms / pathology
  • src-Family Kinases / metabolism*

Substances

  • Fatty Acids
  • src-Family Kinases