NEDD4 Plays Roles in the Maintenance of Breast Cancer Stem Cell Characteristics.

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.