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nature portfolio scientific research permissions reprints special diet services privacy policy nr4a1-activated tgf-β/smad signalling regulating tgf-β/smad signalling tgf-β-induced epithelial-mesenchymal transition tgf-β-driven tumour progression36 facilitate tgf-β/smad signalling potentiating tgf-β/smad signalling author information authors nr4a1-depleted mda-mb-231/mcherry cells promote tgf-β-mediated emt smad3-smad4-driven transcriptional reporter smad7/arkadia/rnf12/axin2 complex endogenously nr4a1 potentiated tgf-β-induced open biosystems tgf-β-induced transcriptional response alexafluor593-labelled anti-rabbit antibody carboxy-terminal ligand-binding domain23 mcf10a-ras-transformed cell line advertising putative ngfi-b-response elements tgf-β/smad signal activation pro-oncogenic tgf-β signalling tgf-β-induced phospho-smad2 full access specific ngfi-b-response element tgf-β-induced epithelial tgf-β/smad signalling tgf-β-smad signalling social media activating tgf-β signalling axin2-induced smad3/smad4 response tgf-β-induced emt tgf-β receptor signalling fundamental research funds nr4a1-depleted mda-mb-231 cells tgf-β/smad activation tgf-β-induced effects tgf-β-induced expression tgf-β-dependent manner caga-luc transcriptional reporter tgf-β pathway acts activated tgf-β type smad7/pai-1/ctgf/cxcr4 expression jak1/stat1-mediated pathway aberrant force-induced osteoarthritis mitigating tgf-β signalling6

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         headline:Nuclear receptor NR4A1 promotes breast cancer invasion and metastasis by activating TGF-β signalling
         description: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. The TGF-β signalling pathway promotes cancer progression in late stage breast cancer, but how the pathway is activated is not always clear. In this study, Zhou et al.identify that the expression of nuclear receptor NR4A1 is induced by inflammation and is an activator of TGF-β-induced metastasis.
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      headline:Nuclear receptor NR4A1 promotes breast cancer invasion and metastasis by activating TGF-β signalling
      description: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. The TGF-β signalling pathway promotes cancer progression in late stage breast cancer, but how the pathway is activated is not always clear. In this study, Zhou et al.identify that the expression of nuclear receptor NR4A1 is induced by inflammation and is an activator of TGF-β-induced metastasis.
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         name:Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
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      name:Leiden University Medical Center
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         name:Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
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      address:
         name:Novartis Institutes for Biomedical Research, Cambridge, USA
         type:PostalAddress
      name:The University of Melbourne, The Royal Melbourne Hospital 5th Floor Clinical Science Building
      address:
         name:Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital 5th Floor Clinical Science Building, Parkville, Victoria, Australia
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      name:Life Sciences Institute, Zhejiang University
      address:
         name:Life Sciences Institute, Zhejiang University, Hangzhou, China
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      name:Life Sciences Institute, Zhejiang University
      address:
         name:Life Sciences Institute, Zhejiang University, Hangzhou, China
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      name:Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center
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         name:Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center, The Netherlands
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            address:
               name:Life Sciences Institute, Zhejiang University, Hangzhou, China
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            name:Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center
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               name:Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center, The Netherlands
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      name:Yvette Drabsch
      affiliation:
            name:Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center
            address:
               name:Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center, The Netherlands
               type:PostalAddress
            type:Organization
      name:Tim J. A. Dekker
      affiliation:
            name:Leiden University Medical Center
            address:
               name:Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
               type:PostalAddress
            type:Organization
      name:Amaya Garcia de Vinuesa
      affiliation:
            name:Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center
            address:
               name:Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center, The Netherlands
               type:PostalAddress
            type:Organization
      name:Yihao Li
      affiliation:
            name:Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center
            address:
               name:Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center, The Netherlands
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      name:Lukas J. A. C. Hawinkels
      affiliation:
            name:Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center
            address:
               name:Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center, The Netherlands
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      name:Kelly-Ann Sheppard
      affiliation:
            name:Novartis Institutes for Biomedical Research
            address:
               name:Novartis Institutes for Biomedical Research, Cambridge, USA
               type:PostalAddress
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      name:Marie-José Goumans
      affiliation:
            name:Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center
            address:
               name:Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center, The Netherlands
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      name:Rodney B. Luwor
      affiliation:
            name:The University of Melbourne, The Royal Melbourne Hospital 5th Floor Clinical Science Building
            address:
               name:Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital 5th Floor Clinical Science Building, Parkville, Victoria, Australia
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      affiliation:
            name:Academic Medical Center, K1-113, University of Amsterdam
            address:
               name:Academic Medical Center, K1-113, University of Amsterdam, Amsterdam, The Netherlands
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      name:Wilma E. Mesker
      affiliation:
            name:Leiden University Medical Center
            address:
               name:Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
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      name:Rob A. E. M. Tollenaar
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            name:Leiden University Medical Center
            address:
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      name:Peter Devilee
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            name:Leiden University Medical Center
            address:
               name:Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
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            type:Organization
      name:Chris X. Lu
      affiliation:
            name:Novartis Institutes for Biomedical Research
            address:
               name:Novartis Institutes for Biomedical Research, Cambridge, USA
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      name:Hongjian Zhu
      affiliation:
            name:The University of Melbourne, The Royal Melbourne Hospital 5th Floor Clinical Science Building
            address:
               name:Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital 5th Floor Clinical Science Building, Parkville, Victoria, Australia
               type:PostalAddress
            type:Organization
      name:Long Zhang
      affiliation:
            name:Life Sciences Institute, Zhejiang University
            address:
               name:Life Sciences Institute, Zhejiang University, Hangzhou, China
               type:PostalAddress
            type:Organization
      email:[email protected]
      name:Peter ten Dijke
      affiliation:
            name:Life Sciences Institute, Zhejiang University
            address:
               name:Life Sciences Institute, Zhejiang University, Hangzhou, China
               type:PostalAddress
            type:Organization
            name:Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center
            address:
               name:Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center, The Netherlands
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Life Sciences Institute, Zhejiang University, Hangzhou, China
      name:Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center, The Netherlands
      name:Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center, The Netherlands
      name:Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
      name:Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center, The Netherlands
      name:Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center, The Netherlands
      name:Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center, The Netherlands
      name:Novartis Institutes for Biomedical Research, Cambridge, USA
      name:Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center, The Netherlands
      name:Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital 5th Floor Clinical Science Building, Parkville, Victoria, Australia
      name:Academic Medical Center, K1-113, University of Amsterdam, Amsterdam, The Netherlands
      name:Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
      name:Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
      name:Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
      name:Novartis Institutes for Biomedical Research, Cambridge, USA
      name:Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital 5th Floor Clinical Science Building, Parkville, Victoria, Australia
      name:Life Sciences Institute, Zhejiang University, Hangzhou, China
      name:Life Sciences Institute, Zhejiang University, Hangzhou, China
      name:Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center, The Netherlands
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