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

Abstract

Background: Triple-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.Methods: Using 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.Results: The 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. Conclusions: These data suggest the previously unrecognized roles of ADAM10 in contributing to the progression and chemo-resistance of TNBC.

Anchorless risk or released benefit? An updated view on the ADAM10-mediated shedding of the prion protein

“…Previous studies mostly focussed on ADAM10's role in extracellular matrix degradation for angiogenesis and metastasis or on its processing of cellular substrates regulating differentiation and cancer cell survival, yet did not consider or reveal any link to PrP (Crawford et al 2009;Dempsey 2017;Ostalecki et al 2017;Smith et al 2020). However, this may now change given that a recent report found both, PrP and its sheddase, to be associated in the pathogenic process of breast cancer progression (Cheng et al 2021). From the combination of elevated PrP levels and increased ADAM10 expression/activity found in various cancer types, one can anticipate that sPrP, the product likely generated by this molecular encounter, may be mechanistically involved in certain oncogenic processes.…”

Dysregulation of ADAM10 shedding activity in naked mole-rat fibroblasts is due to deficient phosphatidylserine externalisation

“…Patients with cancer have higher levels of CD44 cleavage (Okamoto et al, 2002; Yamane et al, 1999). ADAM10 is one of the metalloproteases that cleaves extracellular CD44 (Anderegg et al, 2009; Murai et al, 2006; Nagano et al, 2004; Pan et al, 2012) and is involved in the chemo-resistance of breast cancer cells (Cheng et al, 2021). Interestingly, our data shows that IM, which is well characterised as being able to induce ADAM10 shedding activity (Maretzky et al, 2005; Reiss and Bhakdi, 2012), only does so in the oncogenic NMR SV40-Ras skin fibroblasts, but not in NPSF.…”

Calcium Phosphorus Nanoparticles Coloaded with Paclitaxel and ADAM‐10‐siRNA for the Treatment of Triple Negative Breast Cancer

“…A disintegrin and metalloproteinase 10 (ADAM10) is a member of ADAM sheddases, which belong to matrix metalloproteinases (MMPs) [13]. ADAM family members are uniquely structured cell surface proteins with potential adhesion and protease domains [14]. This gene encodes a member of the ADAM family that cleaves a variety of proteins, including TNF-α and E-cadherin [15].…”