TY - JOUR
T1 - Nuclear receptor NR4A1 promotes breast cancer invasion and metastasis by activating TGF-β signalling
AU - Zhou, Fangfang
AU - Drabsch, Yvette
AU - Dekker, Tim J. A.
AU - de Vinuesa, Amaya Garcia
AU - Li, Yihao
AU - Hawinkels, Lukas J. A. C.
AU - Sheppard, Kelly-Ann
AU - Goumans, Marie-José
AU - Luwor, Rodney B.
AU - de Vries, Carlie J.
AU - Mesker, Wilma E.
AU - Tollenaar, Rob A. E. M.
AU - Devilee, Peter
AU - Lu, Chris X.
AU - Zhu, Hongjian
AU - Zhang, Long
AU - Dijke, Peter Ten
PY - 2014
Y1 - 2014
N2 - 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
AB - 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
U2 - https://doi.org/10.1038/ncomms4388
DO - https://doi.org/10.1038/ncomms4388
M3 - Article
C2 - 24584437
SN - 2041-1723
VL - 5
SP - 3388-(13 p.)
JO - Nature communications
JF - Nature communications
ER -