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

Jessica C. Casciano, Caroline Perry, Adam J. Cohen-Nowak, Katelyn D. Miller, Johan Vande Voorde, Qifeng Zhang, Susan Chalmers, Mairi E. Sandison, Qin Lui, Ann Hedley, Tony McBryan, Hsin-Yao Tang, Nicole Gorman, Thomas Beer, David W. Speicher, Peter D. Adams, Xuefeng Lui, Richard Schlegel, John G. McCarron, Michael J. O. WakelamEyal Gottlieb, Andrew V. Kossenkov, Zachary T. Schug

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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.

Original languageEnglish
Pages (from-to)868-884
Number of pages17
JournalBritish Journal of Cancer
Volume122
Issue number6
Early online date16 Jan 2020
DOIs
Publication statusPublished - 17 Mar 2020

Keywords

  • claudin-low breast cancer
  • MYC
  • calcium signaling
  • fatty acid oxidation
  • CD36
  • CAMKK2
  • cell migration

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Cite this

Casciano, J. C., Perry, C., Cohen-Nowak, A. J., Miller, K. D., Voorde, J. V., Zhang, Q., Chalmers, S., Sandison, M. E., Lui, Q., Hedley, A., McBryan, T., Tang, H-Y., Gorman, N., Beer, T., Speicher, D. W., Adams, P. D., Lui, X., Schlegel, R., McCarron, J. G., ... Schug, Z. T. (2020). MYC regulates fatty acid metabolism through a multigenic program in claudin-low triple negative breast cancer. British Journal of Cancer, 122(6), 868-884. https://doi.org/10.1038/s41416-019-0711-3