MYC regulates fatty acid metabolism through a multigenic program in claudin-low triple negative breast cancer

Casciano, Jessica C. and Perry, Caroline and Cohen-Nowak, Adam J. and Miller, Katelyn D. and Voorde, Johan Vande and Zhang, Qifeng and Chalmers, Susan and Sandison, Mairi E. and Lui, Qin and Hedley, Ann and McBryan, Tony and Tang, Hsin-Yao and Gorman, Nicole and Beer, Thomas and Speicher, David W. and Adams, Peter D. and Lui, Xuefeng and Schlegel, Richard and McCarron, John G. and Wakelam, Michael J. O. and Gottlieb, Eyal and Kossenkov, Andrew V. and Schug, Zachary T. (2020) MYC regulates fatty acid metabolism through a multigenic program in claudin-low triple negative breast cancer. British Journal of Cancer, 122 (6). pp. 868-884. ISSN 1532-1827

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    Abstract

    Background: Recent studies have suggested that fatty acid oxidation (FAO) is a key metabolic pathway for the growth of triple negative breast cancers (TNBCs), particularly those that have high expression of MYC. However, the underlying mechanism by which MYC promotes FAO remains poorly understood. Methods: We used a combination of metabolomics, transcriptomics, bioinformatics, and microscopy to elucidate a potential mechanism by which MYC regulates FAO in TNBC. Results: We propose that MYC induces a multigenic program that involves changes in intracellular calcium signalling and fatty acid metabolism. We determined key roles for fatty acid transporters (CD36), lipases (LPL), and kinases (PDGFRB, CAMKK2, and AMPK) that each contribute to promoting FAO in human mammary epithelial cells that express oncogenic levels of MYC. Bioinformatic analysis further showed that this multigenic program is highly expressed and predicts poor survival in the claudin-low molecular subtype of TNBC, but not other subtypes of TNBCs, suggesting that efforts to target FAO in the clinic may best serve claudin-low TNBC patients. Conclusion: We identified critical pieces of the FAO machinery that have the potential to be targeted for improved treatment of patients with TNBC, especially the claudin-low molecular subtype.