Abstract
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.
Highlights
Breast cancer (BC) is the most common and malignant cancer in women [1] and classified into three subtypes depending on certain molecular biomarkers [2]: estrogen receptor (ER)/progesterone receptor (PR)-positive, HER2-positive, and triple-negative breast cancers (TNBCs)
The KM plotter revealed that the survival rate of patients with a high expression of NEDD4 was shorter than that of patients with a low expression of NEDD4 in HER2-positive (HER2+) and TNBC, which have been known as relatively aggressive breast cancers (Figure 1A)
The proliferation and the migration of MDA-MB231 are decreased, and the expression of breast cancer stem cells (BCSCs) markers and the ability to form mammosphere are significantly reduced by NEDD4 knockdown (Figure 6)
Summary
Breast cancer (BC) is the most common and malignant cancer in women [1] and classified into three subtypes depending on certain molecular biomarkers [2]: estrogen receptor (ER)/progesterone receptor (PR)-positive, HER2-positive, and triple-negative breast cancers (TNBCs). The HER2-positive breast cancers comprise 10–20% of breast cancer patients and have a worse diagnosis than ER/PRpositive breast cancers [3]. These two types of breast cancers are responsive to ER/PR and HER2-targeted therapy, which blocks their downstream signal activation. TNBC, which lacks ER/PR and HER2 on the surface of the cancer cells, occupies 15–20% of all breast cancer patients and has a worse outcome compared to ER/PR-positive and HER2-positive subtypes [4]. Among the six subtypes of TNBCs, the stem cell-like group has a completely distinguished expression pattern of molecular signatures compared to ER/PR- and HER2-positive breast cancers
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