Transforming growth factor β/NR4A1-inducible breast cancer cell migration and epithelial-tomesenchymal transition is p38α (mitogenactivated protein kinase 14) dependent

Erik Hedrick, Stephen Safe

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Transforming growth factor β (TGF-β)-induced migration of triplenegative breast cancer (TNBC) cells is dependent on nuclear export of the orphan receptor NR4A1, which plays a role in proteasome-dependent degradation of SMAD7. In this study, we show that TGF-β induces p38α (mitogen-activated protein kinase 14 [MAPK14]), which in turn phosphorylates NR4A1, resulting in nuclear export of the receptor. TGF-βenchymal transition (EMT) and induction of β-catenin in TNBC cells, and these TGF-β-induced responses and nuclear export of NR4A1 are blocked by NR4A1 antagonists, the p38 inhibitor SB202190, and kinase-dead [p38(KD)] and dominant-negative [p38(DN)] forms of p38 α. Inhibition of NR4A1 nuclear export results in nuclear export of TGF-β-induced β-catenin, which then undergoes proteasome-dependent degradation. TGF-β-induced β-catenin also regulates NR4A1 expression through formation of the β-catenin-TCF-3/TCF-4/LEF-1 complex on the NR4A1 promoter. Thus, TGF-β-induced nuclear export of NR4A1 in TNBC cells plays an essential role in cell migration, SMAD7 degradation, EMT, and induction of β-catenin, and all of these pathways are inhibited by bis-indole-derived NR4A1 antagonists that inhibit nuclear export of the receptor and thereby block TGF-β-induced migration and EMT.

Original languageEnglish (US)
Article numbere00306-17
JournalMolecular and Cellular Biology
Volume37
Issue number18
DOIs
StatePublished - Sep 1 2017

Keywords

  • Breast cancer
  • Migration
  • NR4A1
  • P38
  • P38 kinases
  • TGF-beta
  • TGF-β

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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