NR4A1 Antagonists Inhibit 1-Integrin-Dependent Breast Cancer Cell Migration.
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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 (TGF-) signaling. Results of RNA interference studies demonstrate that basal migration of aggressive SKBR3 and MDA-MB-231 breast cancer cells is TGF- independent and dependent on regulation of 1-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--induced migration of MDA-MB-231 cells by blocking nuclear export of NR4A1, which is an essential step in TGF--induced cell migration. We also observed that NR4A1 regulates expression of both 1- and 3-integrins, and unlike other 1-integrin inhibitors which induce prometastatic 3-integrin, NR4A1 antagonists inhibit expression of both 1- and 3-integrin, demonstrating a novel mechanism-based approach for targeting integrins and integrin-dependent breast cancer metastasis.
author list (cited authors)
Hedrick, E., Lee, S., Doddapaneni, R., Singh, M., & Safe, S.
complete list of authors
Hedrick, Erik||Lee, Syng-Ook||Doddapaneni, Ravi||Singh, Mandip||Safe, Stephen