Journal article
Nuclear receptor NR4A1 promotes breast cancer invasion and metastasis by activating TGF-β signalling
FF Zhou, Y Drabsch, TJA Dekker, AG De Vinuesa, Y Li, LJAC Hawinkels, KA Sheppard, MJ Goumans, RB Luwor, CJ De Vries, WE Mesker, RAEM Tollenaar, P Devilee, CX Lu, H Zhu, L Zhang, PT Ten Dijke
Nature Communications | Published : 2014
DOI: 10.1038/ncomms4388
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 ..
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Awarded by Cancer Genomics Centre
Funding Acknowledgements
We are grateful to our colleagues for helpful discussions. We thank Martijn Rabelink for providing shRNA lenti constructs, Craig Mickanin for high-throughput screening of short interfering RNAs and expression constructs, Patricia Olofson for help with bioluminescent imaging, Maarten van Dinther and Midory Thorikay for expert technical assistance, and Kohei Miyazono and Shengcai Lin for reagents. This work was supported by grants from the Netherlands organization for scientific research (VICI 016.066.606), Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics to P.t.D. and Bas Mulder Award 2011 (UL2011 5051) to L.J.A.C.H. This work was supported by Key Construction Program of the National '985' Project and Zhejiang University Special Fund for Fundamental Research, as well as the Fundamental Research Funds for the Central Universities.