NR4A1 Antagonists Inhibit beta 1-Integrin-Dependent Breast Cancer Cell Migration

作者：Hedrick Erik; Lee Syng Ook; Doddapaneni Ravi; Singh Mandip; Safe Stephen^*

来源：Molecular and Cellular Biology, 2016, 36(9): 1383-1394.

DOI：10.1128/MCB.00912-15

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 beta (TGF-beta) signaling. Results of RNA interference studies demonstrate that basal migration of aggressive SKBR3 and MDA-MB-231 breast cancer cells is TGF-beta independent and dependent on regulation of beta 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-pPhCO(2)Me)] analog. The NR4A1 antagonists also inhibited TGF-beta-induced migration of MDA-MB-231 cells by blocking nuclear export of NR4A1, which is an essential step in TGF-beta-induced cell migration. We also observed that NR4A1 regulates expression of both beta 1- and beta 3-integrins, and unlike other beta 1-integrin inhibitors which induce prometastatic beta 3-integrin, NR4A1 antagonists inhibit expression of both beta 1- and beta 3-integrin, demonstrating a novel mechanism-based approach for targeting integrins and integrin-dependent breast cancer metastasis.

• 出版日期2016-5