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Nuclear receptor NR4A1 promotes breast cancer invasion and metastasis by activating TGF-β signalling

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  • FangFang Zhou

    (Life Sciences Institute, Zhejiang University
    Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center)

  • Yvette Drabsch

    (Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center)

  • Tim J. A. Dekker

    (Leiden University Medical Center)

  • Amaya Garcia de Vinuesa

    (Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center)

  • Yihao Li

    (Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center)

  • Lukas J. A. C. Hawinkels

    (Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center)

  • Kelly-Ann Sheppard

    (Novartis Institutes for Biomedical Research)

  • Marie-José Goumans

    (Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center)

  • Rodney B. Luwor

    (The University of Melbourne, The Royal Melbourne Hospital 5th Floor Clinical Science Building)

  • Carlie J. de Vries

    (Academic Medical Center, K1-113, University of Amsterdam)

  • Wilma E. Mesker

    (Leiden University Medical Center)

  • Rob A. E. M. Tollenaar

    (Leiden University Medical Center)

  • Peter Devilee

    (Leiden University Medical Center)

  • Chris X. Lu

    (Novartis Institutes for Biomedical Research)

  • Hongjian Zhu

    (The University of Melbourne, The Royal Melbourne Hospital 5th Floor Clinical Science Building)

  • Long Zhang

    (Life Sciences Institute, Zhejiang University)

  • Peter ten Dijke

    (Life Sciences Institute, Zhejiang University
    Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center)

Abstract

In advanced cancers, the TGF-β pathway acts as an oncogenic factor and is considered to be a therapeutic target. Here using a genome-wide cDNA screen, we identify nuclear receptor NR4A1 as a strong activator of TGF-β signalling. NR4A1 promotes TGF-β/SMAD signalling by facilitating AXIN2–RNF12/ARKADIA-induced SMAD7 degradation. NR4A1 interacts with SMAD7 and AXIN2, and potently and directly induces AXIN2 expression. Whereas loss of NR4A1 inhibits TGF-β-induced epithelial-to-mesenchymal transition and metastasis, slight NR4A1 ectopic expression stimulates metastasis in a TGF-β-dependent manner. Importantly, inflammatory cytokines potently induce NR4A1 expression, and potentiate TGF-β-mediated breast cancer cell migration, invasion and metastasis in vitro and in vivo. Notably, NR4A1 expression is elevated in breast cancer patients with high immune infiltration and its expression weakly correlates with phosphorylated SMAD2 levels, and is an indicator of poor prognosis. Our results uncover inflammation-induced NR4A1 as an important determinant for hyperactivation of pro-oncogenic TGF-β signalling in breast cancer.

Suggested Citation

  • FangFang Zhou & Yvette Drabsch & Tim J. A. Dekker & Amaya Garcia de Vinuesa & Yihao Li & Lukas J. A. C. Hawinkels & Kelly-Ann Sheppard & Marie-José Goumans & Rodney B. Luwor & Carlie J. de Vries & Wil, 2014. "Nuclear receptor NR4A1 promotes breast cancer invasion and metastasis by activating TGF-β signalling," Nature Communications, Nature, vol. 5(1), pages 1-13, May.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4388
    DOI: 10.1038/ncomms4388
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    Cited by:

    1. Andrej Paluda & Adam J. Middleton & Claudia Rossig & Peter D. Mace & Catherine L. Day, 2022. "Ubiquitin and a charged loop regulate the ubiquitin E3 ligase activity of Ark2C," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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