Jeon Seon-Ae, Kim Dong Wook, Lee Da-Bin, Cho Je-Yoel
Department of Veterinary Biochemistry, BK21 Plus and Research Institute for Veterinary Science, School of Veterinary Medicine, Seoul National University, Seoul, South Korea.
Front Oncol. 2020 Sep 2;10:1680. doi: 10.3389/fonc.2020.01680. eCollection 2020.
Triple-negative breast cancer (TNBC) is the most aggressive type with poor prognosis among the breast cancers and has a high population of cancer stem cells (CSCs), which are the main target to cure and inhibit TNBC. In this study, we examined the role of neural precursor cell expressed developmentally downregulated protein 4 (NEDD4) in the proliferation, migration, and CSC characteristics of MDA-MB-231, a TNBC cell line. Interestingly, the Kaplan-Meier plotter showed that the survival rate of patients with a higher expression level of NEDD4 was significantly shorter than those of patients with a lower expression only in relatively aggressive and higher stage (grade 3) breast cancer patients. The knockdown of NEDD4 drastically decreased the proliferation, migration, and mammosphere formation in MDA-MB-231 cells. A proteomic analysis revealed the alteration of CSC-related proteins; notably, Myc targets stem cell-like signatures in siNEDD4-treated MDA-MB-231. An immunoassay also showed that the expression and the activity of breast CSC markers are decreased in NEDD4-deleted MDA-MB-231. Taken together, these results indicate that NEDD4 is involved in the maintenance of populations and characteristics of breast CSCs.
三阴性乳腺癌（TNBC）是乳腺癌中最具侵袭性且预后较差的类型，并且具有大量的癌症干细胞（CSC），而这些干细胞是治愈和抑制TNBC的主要靶点。在本研究中，我们检测了神经前体细胞表达的发育下调蛋白4（NEDD4）在TNBC细胞系MDA-MB-231的增殖、迁移及CSC特性中的作用。有趣的是，Kaplan-Meier生存曲线分析显示，仅在相对侵袭性较高和分期较晚（3级）的乳腺癌患者中，NEDD4表达水平较高的患者生存率显著低于表达水平较低的患者。敲低NEDD4可显著降低MDA-MB-231细胞的增殖、迁移及乳腺球形成。蛋白质组学分析揭示了CSC相关蛋白的改变；值得注意的是，在经siNEDD4处理的MDA-MB-231中，Myc靶向干细胞样特征。免疫分析还显示，在缺失NEDD4的MDA-MB-231中，乳腺CSC标志物的表达和活性降低。综上所述，这些结果表明NEDD4参与维持乳腺CSC的数量和特性。
