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MYC regulates fatty acid metabolism through a multigenic program in claudin-low triple negative breast cancer.
Casciano, Jessica C; Perry, Caroline; Cohen-Nowak, Adam J; Miller, Katelyn D; Vande Voorde, Johan; Zhang, Qifeng; Chalmers, Susan; Sandison, Mairi E; Liu, Qin; Hedley, Ann; McBryan, Tony; Tang, Hsin-Yao; Gorman, Nicole; Beer, Thomas; Speicher, David W; Adams, Peter D; Liu, Xuefeng; Schlegel, Richard; McCarron, John G; Wakelam, Michael J O; Gottlieb, Eyal; Kossenkov, Andrew V; Schug, Zachary T.
Affiliation
  • Casciano JC; The Wistar Institute, Molecular and Cellular Oncogenesis, 3601 Spruce Street, Philadelphia, PA, 19104, USA.
  • Perry C; The Wistar Institute, Molecular and Cellular Oncogenesis, 3601 Spruce Street, Philadelphia, PA, 19104, USA.
  • Cohen-Nowak AJ; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • Miller KD; The Wistar Institute, Molecular and Cellular Oncogenesis, 3601 Spruce Street, Philadelphia, PA, 19104, USA.
  • Vande Voorde J; The Wistar Institute, Molecular and Cellular Oncogenesis, 3601 Spruce Street, Philadelphia, PA, 19104, USA.
  • Zhang Q; The Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK.
  • Chalmers S; The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK.
  • Sandison ME; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, SIPBS Building, 161 Cathedral Street, Glasgow, G4 0RE, UK.
  • Liu Q; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, SIPBS Building, 161 Cathedral Street, Glasgow, G4 0RE, UK.
  • Hedley A; Department of Biomedical Engineering, University of Strathclyde, Wolfson Centre, 106 Rottenrow, Glasgow, G4 0NW, UK.
  • McBryan T; The Wistar Institute, Molecular and Cellular Oncogenesis, 3601 Spruce Street, Philadelphia, PA, 19104, USA.
  • Tang HY; The Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK.
  • Gorman N; The Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK.
  • Beer T; Institute of Cancer Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, G61 1BD, UK.
  • Speicher DW; The Wistar Institute, Molecular and Cellular Oncogenesis, 3601 Spruce Street, Philadelphia, PA, 19104, USA.
  • Adams PD; The Wistar Institute, Molecular and Cellular Oncogenesis, 3601 Spruce Street, Philadelphia, PA, 19104, USA.
  • Liu X; The Wistar Institute, Molecular and Cellular Oncogenesis, 3601 Spruce Street, Philadelphia, PA, 19104, USA.
  • Schlegel R; The Wistar Institute, Molecular and Cellular Oncogenesis, 3601 Spruce Street, Philadelphia, PA, 19104, USA.
  • McCarron JG; Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA.
  • Wakelam MJO; Center for Cell Reprogramming, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3900 Reservoir Road, Washington D.C., 20057, USA.
  • Gottlieb E; Center for Cell Reprogramming, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3900 Reservoir Road, Washington D.C., 20057, USA.
  • Kossenkov AV; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, SIPBS Building, 161 Cathedral Street, Glasgow, G4 0RE, UK.
  • Schug ZT; The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK.
Br J Cancer ; 122(6): 868-884, 2020 03.
Article in En | MEDLINE | ID: mdl-31942031
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Proto-Oncogene Proteins c-myc / Fatty Acids / Metabolomics / Claudins / Triple Negative Breast Neoplasms Limits: Female / Humans Language: En Journal: Br J Cancer Year: 2020 Document type: Article Affiliation country:
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Proto-Oncogene Proteins c-myc / Fatty Acids / Metabolomics / Claudins / Triple Negative Breast Neoplasms Limits: Female / Humans Language: En Journal: Br J Cancer Year: 2020 Document type: Article Affiliation country: