NR4A1 antagonists inhibit β1-integrin-dependent breast cancer cell migration

Erik Hedrick, Syng Ook Lee, Ravi Doddapaneni, Mandip Singh, Stephen Safe

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Overexpression of the nuclear receptor 4A1 (NR4A1) in breast cancer patients is a prognostic factor for decreased survival and increased metastasis, and this has been linked to NR4A1-dependent regulation of transforming growth factor β (TGF-β) signaling. Results of RNA interference studies demonstrate that basal migration of aggressive SKBR3 and MDA-MB-231 breast cancer cells is TGF-β independent and dependent on regulation of β1-integrin gene expression by NR4A1 which can be inhibited by the NR4A1 antagonists 1,1-bis(3=-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) and a related p-carboxymethylphenyl [1,1-bis(3=-indolyl)-1-(p-carboxymethylphenyl)methane (DIM-C-pPhCO2Me)] analog. The NR4A1 antagonists also inhibited TGF-β-induced migration of MDA-MB-231 cells by blocking nuclear export of NR4A1, which is an essential step in TGF-β-induced cell migration. We also observed that NR4A1 regulates expression of both β1- and β3-integrins, and unlike other β1-integrin inhibitors which induce prometastatic β3-integrin, NR4A1 antagonists inhibit expression of both β1- and β3-integrin, demonstrating a novel mechanism-based approach for targeting integrins and integrin-dependent breast cancer metastasis.

Original languageEnglish (US)
Pages (from-to)1383-1394
Number of pages12
JournalMolecular and Cellular Biology
Volume36
Issue number9
DOIs
StatePublished - May 1 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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