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Nat Commun. 2014 Mar 3;5:3388. doi: 10.1038/ncomms4388.

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

Author information

1
1] Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China [2] Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center, Postbus 9600, 2300 RC Leiden, The Netherlands.
2
Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center, Postbus 9600, 2300 RC Leiden, The Netherlands.
3
Department of Surgery, Leiden University Medical Center, Postbus 9600, 2300 RC Leiden, The Netherlands.
4
Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
5
Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital 5th Floor Clinical Science Building, Parkville, Victoria 3050, Australia.
6
Academic Medical Center, K1-113, University of Amsterdam, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands.
7
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
8
Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China.

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.

PMID:
24584437
DOI:
10.1038/ncomms4388
[Indexed for MEDLINE]

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