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

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, Wilma E. Mesker, Rob A. E. M. Tollenaar, Peter Devilee, Chris X. Lu, Hongjian Zhu, Long Zhang () and Peter ten Dijke ()
Additional contact information
FangFang Zhou: Life Sciences Institute, Zhejiang University
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

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4388

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