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Br J Cancer. 2015 Jun 9;112(12):1895-903. doi: 10.1038/bjc.2015.163. Epub 2015 May 26.

Targeting ADAM-17 with an inhibitory monoclonal antibody has antitumour effects in triple-negative breast cancer cells.

Author information

1
UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
2
National Institute for Cellular Biotechnology (NICB), Dublin City University, Dublin, Ireland.
3
1] Department of Oncology, Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK [2] Cell Communication Team, Division of Cancer Biology, The Institute of Cancer Research, London, UK.
4
Department of Oncology, Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK.
5
Department of Medical Oncology, St Vincent's University Hospital, Dublin, Ireland.
6
1] UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland [2] UCD Clinical Research Centre, St Vincent's University Hospital, Dublin, Ireland.

Abstract

BACKGROUND:

Identification and validation of a targeted therapy for triple-negative breast cancer (TNBC), that is, breast cancers negative for oestrogen receptors, progesterone receptors and HER2 amplification, is currently one of the most urgent problems in breast cancer treatment. EGFR is one of the best-validated driver genes for TNBC. EGFR is normally activated following the release of ligands such as TGFα, mediated by the two MMP-like proteases ADAM (a disintegrin and metalloproteinase)-10 and ADAM-17. The aim of this study was to investigate the antitumour effects of a monoclonal antibody against ADAM-17 on an in vitro model of TNBC.

METHODS:

We investigated an inhibitory cross-domain humanised monoclonal antibody targeting both the catalytic domain and the cysteine-rich domain of ADAM17-D1(A12) in the HCC1937 and HCC1143 cell lines.

RESULTS:

D1(A12) was found to significantly inhibit the release of TGFα, and to decrease downstream EGFR-dependent cell signalling. D1(A12) treatment reduced proliferation in two-dimensional clonogenic assays, as well as growth in three-dimensional culture. Furthermore, D1(A12) reduced invasion of HCC1937 cells and decreased migration of HCC1143 cells. Finally, D1(A12) enhanced cell death in HCC1143 cells.

CONCLUSION:

Our in vitro findings suggest that targeting ADAM-17 with D1(A12) may have anticancer activity in TNBC cells.

PMID:
26010411
PMCID:
PMC4580380
DOI:
10.1038/bjc.2015.163
[Indexed for MEDLINE]
Free PMC Article

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