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GLUT1 inhibition blocks growth of RB1-positive triple negative breast cancer

Author

Listed:
  • Qin Wu

    (University of Toronto
    University Health Network
    University of Toronto)

  • Wail ba-alawi

    (University Health Network
    University of Toronto)

  • Genevieve Deblois

    (University Health Network)

  • Jennifer Cruickshank

    (Princess Margaret Cancer Centre)

  • Shili Duan

    (University Health Network)

  • Evelyne Lima-Fernandes

    (University of Toronto
    University Health Network)

  • Jillian Haight

    (Princess Margaret Cancer Centre)

  • Seyed Ali Madani Tonekaboni

    (University Health Network
    University of Toronto)

  • Anne-Marie Fortier

    (McGill University)

  • Hellen Kuasne

    (McGill University)

  • Trevor D. McKee

    (University Health Network
    STTARR Innovation Facility)

  • Hassan Mahmoud

    (University Health Network
    University of Toronto
    Benha University)

  • Michelle Kushida

    (The Hospital for Sick Children)

  • Sarina Cameron

    (University Health Network
    University of Toronto)

  • Nergiz Dogan-Artun

    (University Health Network
    University of Toronto)

  • WenJun Chen

    (University of Toronto)

  • Yan Nie

    (University of Toronto
    University Health Network
    University of Toronto)

  • Lan Xin Zhang

    (University of Toronto)

  • Ravi N. Vellanki

    (University Health Network)

  • Stanley Zhou

    (University Health Network
    University of Toronto)

  • Panagiotis Prinos

    (University of Toronto)

  • Bradly G. Wouters

    (University Health Network
    University of Toronto)

  • Peter B. Dirks

    (The Hospital for Sick Children
    University of Toronto
    University of Toronto)

  • Susan J. Done

    (Princess Margaret Cancer Centre)

  • Morag Park

    (McGill University)

  • David W. Cescon

    (Princess Margaret Cancer Centre)

  • Benjamin Haibe-Kains

    (University Health Network
    University of Toronto
    University of Toronto
    Ontario Institue for Cancer Research)

  • Mathieu Lupien

    (University Health Network
    University of Toronto
    Ontario Institue for Cancer Research)

  • Cheryl H. Arrowsmith

    (University of Toronto
    University Health Network
    University of Toronto)

Abstract

Triple negative breast cancer (TNBC) is a deadly form of breast cancer due to the development of resistance to chemotherapy affecting over 30% of patients. New therapeutics and companion biomarkers are urgently needed. Recognizing the elevated expression of glucose transporter 1 (GLUT1, encoded by SLC2A1) and associated metabolic dependencies in TNBC, we investigated the vulnerability of TNBC cell lines and patient-derived samples to GLUT1 inhibition. We report that genetic or pharmacological inhibition of GLUT1 with BAY-876 impairs the growth of a subset of TNBC cells displaying high glycolytic and lower oxidative phosphorylation (OXPHOS) rates. Pathway enrichment analysis of gene expression data suggests that the functionality of the E2F pathway may reflect to some extent OXPHOS activity. Furthermore, the protein levels of retinoblastoma tumor suppressor (RB1) strongly correlate with the degree of sensitivity to GLUT1 inhibition in TNBC, where RB1-negative cells are insensitive to GLUT1 inhibition. Collectively, our results highlight a strong and targetable RB1-GLUT1 metabolic axis in TNBC and warrant clinical evaluation of GLUT1 inhibition in TNBC patients stratified according to RB1 protein expression levels.

Suggested Citation

  • Qin Wu & Wail ba-alawi & Genevieve Deblois & Jennifer Cruickshank & Shili Duan & Evelyne Lima-Fernandes & Jillian Haight & Seyed Ali Madani Tonekaboni & Anne-Marie Fortier & Hellen Kuasne & Trevor D. , 2020. "GLUT1 inhibition blocks growth of RB1-positive triple negative breast cancer," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18020-8
    DOI: 10.1038/s41467-020-18020-8
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    Cited by:

    1. Zhenxing Zhang & Xin Li & Fan Yang & Chao Chen & Ping Liu & Yi Ren & Pengkai Sun & Zixiong Wang & Yongping You & Yi-Xin Zeng & Xinjian Li, 2021. "DHHC9-mediated GLUT1 S-palmitoylation promotes glioblastoma glycolysis and tumorigenesis," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    2. Xijiao Ren & Zhuo Cheng & Jinming He & Xuemei Yao & Yingqi Liu & Kaiyong Cai & Menghuan Li & Yan Hu & Zhong Luo, 2023. "Inhibition of glycolysis-driven immunosuppression with a nano-assembly enhances response to immune checkpoint blockade therapy in triple negative breast cancer," Nature Communications, Nature, vol. 14(1), pages 1-22, December.

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