Hedrick Erik, Lee Syng-Ook, Doddapaneni Ravi, Singh Mandip, Safe Stephen
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas, USA.
Department of Food Science and Technology, Keimyung University, Daegu, Republic of Korea.
Mol Cell Biol. 2016 Apr 15;36(9):1383-94. doi: 10.1128/MCB.00912-15. Print 2016 May.
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.
核受体4A1（NR4A1）在乳腺癌患者中的过表达是生存率降低和转移增加的一个预后因素，这与NR4A1依赖的转化生长因子β（TGF-β）信号调节有关。RNA干扰研究结果表明，侵袭性SKBR3和MDA-MB-231乳腺癌细胞的基础迁移不依赖TGF-β，而是依赖于NR4A1对β1整合素基因表达的调节，而NR4A1拮抗剂1,1-双（3'-吲哚基）-1-（对羟基苯基）甲烷（DIM-C-pPhOH）和一种相关的对羧甲基苯基[1,1-双（3'-吲哚基）-1-（对羧甲基苯基）甲烷（DIM-C-pPhCO2Me）]类似物可抑制这种调节。NR4A1拮抗剂还通过阻断NR4A1的核输出抑制TGF-β诱导的MDA-MB-231细胞迁移，这是TGF-β诱导细胞迁移的一个关键步骤。我们还观察到NR4A1调节β1和β3整合素的表达，与其他诱导促转移β3整合素的β1整合素抑制剂不同，NR4A1拮抗剂抑制β1和β3整合素的表达，这证明了一种基于新机制的靶向整合素和整合素依赖性乳腺癌转移的方法。
