ADAM9 Mediates Triple-Negative Breast Cancer Progression via AKT/NF-κB Pathway.

Rui Zhou,Victor Ma,Mei Tian,S C Cesar Wong,Hong Zhang,Mingrong Zhang,Yujie Sun,Yik-Ka So,Cong Li,Lawrence W C Chan,Wah Cheuk,William C S Cho

doi:10.3389/fmed.2020.00214

Abstract

Upregulation of a disintegrin and metalloprotease 9 (ADAM9) is correlated with progression of cancers, such as prostate, bladder, and pancreatic cancers. However, its role in triple-negative breast cancer (TNBC) is still unclear. Our study aimed to investigate whether ADAM9 is upregulated and promoted the aggressiveness in TNBC. Breast cancer cell lines and patient specimens were used to evaluate the ADAM9 expression by western blotting and immunohistochemistry staining, respectively. Compared with the non-TNBC, ADAM9 expression was significantly increased in TNBC cells and TNBC patient specimens. Based on the data acquired from public databases, the correlation between ADAM9 expression and breast cancer patient survival was analyzed by Kaplan-Meier method. It was shown that ADAM9 overexpression was significantly correlated with poorer survival in patients with TNBC. Furthermore, ADAM9 in TNBC cells was knocked down by small interference RNA and then studied by the MTT/colony formation assay, wound healing assay and transwell invasion assay on the cell proliferation, migration, and invasion, respectively. We found that inhibiting ADAM9 expression suppressed TNBC cell proliferation, migration, and invasion by lowering the activation of AKT/NF-κB pathway. Our results demonstrated that ADAM9 is an important molecule in mediating TNBC aggressiveness and may be a potential useful therapeutic target in TNBC treatment.

Highlights

Triple-negative breast cancer (TNBC) is defined as absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression
To determine whether a disintegrin and metalloprotease 9 (ADAM9) is overexpressed in triple-negative breast cancer (TNBC) primary tumor when compared to non-TNBC primary tumor, we investigated the ADAM9 expression in breast primary tumor and breast cancer cell lines
RT-qPCR result indicated that gene expression level of ADAM9 in MDA-MB-231 was higher than non-TNBC cell lines (Figure 1D)

Summary

Introduction

Triple-negative breast cancer (TNBC) is defined as absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. ADAM9 Overexpression Promotes TNBC Progression including epidermal growth factor receptor (EGFR) inhibitors (Cetuximab), poly (ADP-ribose) polymerase (PARP) inhibitors, and phosphatidylinositol 3-kinase (PI3K) inhibitors, are approved to be used in TNBC clinical trials, no significant improvement have been achieved in phase 3 trials [2, 3]. 21 members of the family have been identified in humans, of which 13 have functional protease activities to release ligands to stimulate cell proliferation and migration [5]. ADAM9, as a member of ADAMs that has functional protease activities, involves in cell-cell interactions and extracellular matrix degradation by binding with integrins including α6β1 and αvβ5 [6, 7]. Whether ADAM9 is upregulated and contributes to the aggressiveness in TNBC still remains unclear

Methods

Results

Conclusion