title: Nuclear receptor NR4A1 promotes breast cancer invasion and metastasis by activating TGF-β signalling.
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.
authors.affiliation: 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.
authors.forename: FangFang
authors.initials: F
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Yvette
authors.initials: Y
authors.lastname: Drabsch
authors.affiliation: Department of Surgery, Leiden University Medical Center, Postbus 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Tim J A
authors.initials: TJ
authors.lastname: Dekker
authors.affiliation: 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.
authors.forename: Amaya Garcia
authors.initials: AG
authors.lastname: de Vinuesa
authors.affiliation: 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.
authors.forename: Yihao
authors.initials: Y
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Lukas J A C
authors.initials: LJ
authors.lastname: Hawinkels
authors.affiliation: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors.forename: Kelly-Ann
authors.initials: KA
authors.lastname: Sheppard
authors.affiliation: 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.
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Goumans
authors.affiliation: Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital 5th Floor Clinical Science Building, Parkville, Victoria 3050, Australia.
authors.forename: Rodney B
authors.initials: RB
authors.lastname: Luwor
authors.affiliation: Academic Medical Center, K1-113, University of Amsterdam, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands.
authors.forename: Carlie J
authors.initials: CJ
authors.lastname: de Vries
authors.affiliation: Department of Surgery, Leiden University Medical Center, Postbus 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Wilma E
authors.initials: WE
authors.lastname: Mesker
authors.affiliation: Department of Surgery, Leiden University Medical Center, Postbus 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Rob A E M
authors.initials: RA
authors.lastname: Tollenaar
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Devilee
authors.affiliation: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors.forename: Chris X
authors.initials: CX
authors.lastname: Lu
authors.affiliation: Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital 5th Floor Clinical Science Building, Parkville, Victoria 3050, Australia.
authors.forename: Hongjian
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Long
authors.initials: L
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Peter Ten
authors.initials: PT
authors.lastname: Dijke
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D005260:Female; D007150:Immunohistochemistry; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis / Q000235:genetics / Q000503:physiopathology*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000235:genetics / Q000502:physiology; D015027:Zebrafish
chemical_list: D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D016212:Transforming Growth Factor beta