4.8 Article

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

Journal

NATURE COMMUNICATIONS
Volume 5, Issue -, Pages -

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms4388

Keywords

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Funding

  1. Netherlands organization for scientific research [VICI 016.066.606]
  2. Cancer Genomics Centre Netherlands
  3. Centre for Biomedical Genetics
  4. Bas Mulder Award [UL2011 5051]
  5. Key Construction Program of the National '985' Project
  6. Zhejiang University Special Fund for Fundamental Research
  7. Fundamental Research Funds for the Central Universities

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In advanced cancers, the T 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-beta signalling. NR4A1 promotes TGF-beta/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-beta-induced epithelial-to-mesenchymal transition and metastasis, slight NR4A1 ectopic expression stimulates metastasis in a TGF-beta-dependent manner. Importantly, inflammatory cytokines potently induce NR4A1 expression, and potentiate TGF-beta-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-b signalling in breast cancer.

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