TY - JOUR
T1 - MYC regulates fatty acid metabolism through a multigenic program in claudin-low triple negative breast cancer
AU - Casciano, Jessica C.
AU - Perry, Caroline
AU - Cohen-Nowak, Adam J.
AU - Miller, Katelyn D.
AU - Vande Voorde, Johan
AU - Zhang, Qifeng
AU - Chalmers, Susan
AU - Sandison, Mairi E.
AU - Liu, Qin
AU - Hedley, Ann
AU - McBryan, Tony
AU - Tang, Hsin Yao
AU - Gorman, Nicole
AU - Beer, Thomas
AU - Speicher, David W.
AU - Adams, Peter D.
AU - Liu, Xuefeng
AU - Schlegel, Richard
AU - McCarron, John G.
AU - Wakelam, Michael J.O.
AU - Gottlieb, Eyal
AU - Kossenkov, Andrew V.
AU - Schug, Zachary T.
N1 - Funding Information:
Funding information This work was supported by grants from Cancer Research UK (A18477; Z.T.S. and E.G.), the W.W. Smith Charitable Trust (C1801; Z.T.S.), the Susan G. Komen Foundation (CCR19608782; Z.T.S.), NIH grant (NCI DP2 CA249950-01; Z.T.S.), the Wistar Institute, NIH grant (NCI P30CA010815), and by metabolomics, genomics, and flow cytometry facilities of the Wistar Institute. H.-Y.T. is supported by NIH grants R50CA221838 and S10OD023586. S.C., M.S., and J.G.M. were supported by Wellcome Trust grant 202924/Z/16/Z. M.J.O.W. is supported by Biotechnology and Biological Sciences Research Council grant BB/P013384/1. P.D.A. is supported by NIH grant P01 AG031862-12.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/3/17
Y1 - 2020/3/17
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85078309521&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85078309521&partnerID=8YFLogxK
U2 - 10.1038/s41416-019-0711-3
DO - 10.1038/s41416-019-0711-3
M3 - Article
C2 - 31942031
AN - SCOPUS:85078309521
SN - 0007-0920
VL - 122
SP - 868
EP - 884
JO - British journal of cancer
JF - British journal of cancer
IS - 6
ER -