ADAM10 is involved in the oncogenic process and chemo-resistance of triple-negative breast cancer via regulating Notch1 signaling pathway, CD44 and PrPc

Yuanyuan Cheng,Zhongwen Zhou,Aiqi Lu,Chenjian Hou,Qian Wu,Lishuang Lin,Xiaomu Hu,Xiaoyan Li,Feng Tang,Zhongqing Chen

doi:10.1186/s12935-020-01727-5

Abstract

BackgroundTriple-negative breast cancer (TNBC) is the most challenging breast cancer subtype to treat, because it is so aggressive with shorter survival. Chemotherapy remains the standard treatment due to the lack of specific and effective molecular targets. The aim of the present study is to investigate the potential roles of A Disintegrin and Metalloproteinase 10 (ADAM10) on TNBC cells and the effects of combining ADAM10 expression and neoadjuvant chemotherapy treatment (NACT) to improve the overall survival in breast cancer patients.MethodsUsing a series of breast cancer cell lines, we measured the expression of ADAM10 and its substrates by quantitative real-time PCR assay (qRT-PCR) and western blot analysis. Cell migration and invasion, cell proliferation, drug sensitivity assay, cell cycle and apoptosis were conducted in MDA-MB-231 cells cultured with ADAM10 siRNA. The effect of ADAM10 down-regulation by siRNA on its substrates was assessed by western blot analysis. We performed immunohistochemical staining for ADAM10 in clinical breast cancer tissues in 94 patients receiving NACT.ResultsThe active form of ADAM10 was highly expressed in TNBC cell lines. Knockdown of ADAM10 in MDA-MB-231 cells led to a significant decrease in cell proliferation, migration, invasion and the IC50 value of paclitaxel and adriamycin, while induced cell cycle arrest and apoptosis. And these changes were correlated with down-regulation of Notch signaling, CD44 and cellular prion protein (PrPc). In clinical breast cancer cases, a high ADAM10 expression in pre-NACT samples was strongly associated with poorer response to NACT and shorter overall survival.ConclusionsThese data suggest the previously unrecognized roles of ADAM10 in contributing to the progression and chemo-resistance of TNBC.

Highlights

Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype to treat, because it is so aggressive with shorter survival
We have found that the active form of A Disintegrin and Metalloproteinase 10 (ADAM10) is highly expressed in TNBC cell lines compared with estrogen receptor (ER) + cell line
The mRNA expression level of ADAM10 was higher in triple-negative cell lines and human epidermal growth factor receptor 2 (HER2) amplified cell line compared to ER + cell lines using quantitative real-time PCR assay (qRT-PCR) assay (Fig. 1b)

Summary

Introduction

Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype to treat, because it is so aggressive with shorter survival. The aim of the present study is to investigate the potential roles of A Disintegrin and Metalloproteinase 10 (ADAM10) on TNBC cells and the effects of combining ADAM10 expression and neoadjuvant chemotherapy treatment (NACT) to improve the overall survival in breast cancer patients. The protein structure of ADAM10 contains an N-terminal signal sequence, a catalytic MMP domain, a disintegrin domain related to cell adhesion, an EGF-like domain, a transmembrane domain, and a cytoplasmic. Dysregulation of ADAM10 activity is associated with pathological processes in some human diseases especially in brain disorders [8]. Activation of ADAM10 aiming at increasing normal PrP breakdown and depleting PrPsc could be seen as putative therapeutic strategy for prion disease [11]

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