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ADAM10: a new player in breast cancer progression?
Date Issued
2015-08-18
Date Available
2019-04-03T08:44:14Z
Abstract
Background: The ADAM proteases are best known for their role in shedding the extracellular domain of transmembrane proteins. Among the transmembrane proteins shed by ADAM10 are notch, HER2, E-cadherin, CD44, L1 and the EGFR ligands, EGF and betacellulin. As cleavage of several of these proteins has been implicated in cancer formation and progression, we hypothesised that ADAM10 is also involved in these processes.
Methods: ADAM10 expression was decreased by RNA interference and the effects of this on cell numbers, invasion and migration were determined. We also examined the effect of ADAM10 inhibition on breast cancer cell line invasion and migration.
Results: Using the triple-negative (TN) breast cancer cell lines, BT20, MDA-MB-231 and the non-TN cell line MDA-MB-453, knockdown of ADAM10 expression significantly decreased in vitro migration (Po0.01; for each cell line). Similarly, treatment with the ADAM10-selective inhibitor GI254023X reduced migration in the three cell lines (for BT20, Po0.001; for MDA-MB-231, P ¼ 0.005; for MDA-MB-453, P ¼ 0.023). In contrast, neither knockdown of ADAM10 nor treatment with the ADAM10-selective inhibitor GI254023X significantly affected cell numbers. Using extracts of primary breast cancers, higher levels of ADAM10 were found more frequently in high-grade vs low-grade tumours (Po0.001) and in oestrogen receptor (ER)-negative compared with ERpositive tumours (P ¼ 0.005). Analysis of pooled publicly available data sets found that high levels of ADAM10 mRNA were associated with adverse outcome in patients with the basal subtype of breast cancer.
Conclusions: Based on our combined cell line and breast cancer extract data, we conclude that ADAM10 is likely to be involved in breast cancer progression, especially in the basal subtype.
Sponsorship
European Commission - Seventh Framework Programme (FP7)
Health Research Board
Irish Cancer Society
Science Foundation Ireland
Other Sponsorship
Cancer Research Ireland Postdoctoral Fellowship
Cancer Clinical Research Trust
Type of Material
Journal Article
Publisher
Cancer Research UK
Journal
British Journal of Cancer
Volume
113
Start Page
945
End Page
951
Copyright (Published Version)
2015 the Authors
Language
English
Status of Item
Peer reviewed
This item is made available under a Creative Commons License
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ADAM10 a new player in breast cancer progression.pdf
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