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

Jun Hyoung Park, Sajna Vithayathil, Santosh Kumar, Pi Lin Sung, Lacey Elizabeth Dobrolecki, Vasanta Putluri, Vadiraja B. Bhat, Salil Kumar Bhowmik, Vineet Gupta, Kavisha Arora, Danli Wu, Efrosini Tsouko, Yiqun Zhang, Suman Maity, Taraka R. Donti, Brett H. Graham, Daniel E. Frigo, Cristian Coarfa, Patricia Yotnda, Nagireddy PutluriArun Sreekumar, Michael T. Lewis, Chad J. Creighton, Lee Jun C Wong, Benny Abraham Kaipparettu

Research output: Contribution to journalArticle

103 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2154-2165
Number of pages12
JournalCell Reports
Volume14
Issue number9
DOIs
StatePublished - Mar 8 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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