NR4A1 Antagonists Inhibit β1-Integrin-Dependent Breast Cancer Cell Migration

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.

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Correction for Hedrick et al., “NR4A1 Antagonists Inhibit β1-Integrin-Dependent Breast Cancer Cell Migration”

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00912-15.

ACKNOWLEDGMENTS

The financial assistance of the National Institutes of Health (P30-ES023512, S. Safe), the DOD-CDRMP (BC103116, M. Singh), Texas AgriLife Research and Sid Kyle endowment, is gratefully acknowledged.

E.H. carried out the in vitro studies and assisted in writing the manuscript. S.-O.L. carried out some of the in vitro studies and initially identified β1-integrin as an NR4A1-regulated gene. R.D. carried out the in vivo studies. M.S. supervised the in vivo studies and carried out data analysis. S.S. developed the C-DIMs as NR4A1 antagonists, supervised the studies, and wrote the manuscript.

We declare that we have no conflicts of interest that would prejudice the impartiality of this research.

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Funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.