ADAM10: a new player in breast cancer progression?
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 (P<0.01; for each cell line). Similarly, treatment with the ADAM10-selective inhibitor GI254023X reduced migration in the three cell lines (for BT20, P<0.001; for MDA-MB-231, P=0.005; for MDA-MB-453, P=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 (P<0.001) and in oestrogen receptor (ER)-negative compared with ER-positive tumours (P=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.
UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.|Education and Research Centre, St. Vincent's University Hospital, Dublin, Ireland.
Maeve
M
Mullooly
UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.|Education and Research Centre, St. Vincent's University Hospital, Dublin, Ireland.
Patricia M
PM
McGowan
Systems Biology Ireland, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
Susan A
SA
Kennedy
National Institute for Cellular Biotechnology (NICB), Dublin City University, Dublin, Ireland.
Stephen F
SF
Madden
National Institute for Cellular Biotechnology (NICB), Dublin City University, Dublin, Ireland.|Department of Medical Oncology, St. Vincent's University Hospital, Dublin, Ireland.
John
J
Crown
National Institute for Cellular Biotechnology (NICB), Dublin City University, Dublin, Ireland.
Norma
N
O' Donovan
UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.|UCD Clinical Research Centre, St. Vincent's University Hospital, Dublin, Ireland.
Michael J
MJ
Duffy
D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002452:Cell Count; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism* / Q000473:pathology
C555398:3-(formylhydroxyamino)-2-(3-phenyl-1-propyl)butanoic acid (2,2-dimethyl-1-methylcarbamoyl-1-propyl)amide; D004151:Dipeptides; D006877:Hydroxamic Acids; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human