ADAM8 expression in invasive breast cancer promotes tumor dissemination and metastasis
Article first published online: 27 DEC 2013
© 2013 The Authors.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
EMBO Molecular Medicine
Volume 6, Issue 2, pages 278–294, February 2014
How to Cite
Romagnoli, M., Mineva, N. D., Polmear, M., Conrad, C., Srinivasan, S., Loussouarn, D., Barillé-Nion, S., Georgakoudi, I., Dagg, Á., McDermott, E. W., Duffy, M. J., McGowan, P. M., Schlomann, U., Parsons, M., Bartsch, J. W. and Sonenshein, G. E. (2014), ADAM8 expression in invasive breast cancer promotes tumor dissemination and metastasis. EMBO Mol Med, 6: 278–294. doi: 10.1002/emmm.201303373
- Issue published online: 7 FEB 2014
- Article first published online: 27 DEC 2013
- Manuscript Accepted: 15 AUG 2013
- Manuscript Revised: 13 AUG 2013
- Manuscript Received: 8 AUG 2013
- NIH. Grant Numbers: P01 ES11624, R01 CA129129
- Irish Cancer Society fellowship . Grant Number: CRF11MCG
- BREAST-PREDICT project of the Irish Cancer Society . Grant Numbers: W81XWH-10-1-1003, RSG-09-174-01-CCE, 08/SRC/B1410
- DOD postdoctoral fellowship. Grant Number: W81XWH-10-1-1003
- Tufts University CTSI award
- American Cancer Society. Grant Number: RSG-09-174-01-CCE
- Cancer Research Technology
- Alfred und Ursula Kulemann-Stiftung
- Science Foundation Ireland . Grant Number: 08/SRC/B1410
- Molecular Therapeutics for Cancer, Ireland
- ADAM8 ;
- cancer progression;
- therapeutic target;
- breast cancer
The transmembrane metalloprotease-disintegrin ADAM8 mediates cell adhesion and shedding of ligands, receptors and extracellular matrix components. Here, we report that ADAM8 is abundantly expressed in breast tumors and derived metastases compared to normal tissue, especially in triple-negative breast cancers (TNBCs). Furthermore, high ADAM8 levels predicted poor patient outcome. Consistently, ADAM8 promoted an aggressive phenotype of TNBC cells in culture. In a mouse orthotopic model, tumors derived from TNBC cells with ADAM8 knockdown failed to grow beyond a palpable size and displayed poor vascularization. Circulating tumor cells and brain metastases were also significantly reduced. Mechanistically, ADAM8 stimulated both angiogenesis through release of VEGF-A and transendothelial cell migration via β1-integrin activation. In vivo, treatment with an anti-ADAM8 antibody from the time of cell inoculation reduced primary tumor burden and metastases. Furthermore, antibody treatment of established tumors profoundly decreased metastases in a resection model. As a non-essential protein under physiological conditions, ADAM8 represents a promising novel target for treatment of TNBCs, which currently lack targeted therapies and frequently progress with fatal dissemination.
The transmembrane protein ADAM8 is shown to be a crucial player in multiple steps of breast tumorigenesis, notably in angiogenesis and cancer cell adhesion to the endothelium. The results validate ADAM8 as novel target for the treatment of aggressive triple-negative breast cancer
- The transmembrane ADAM8 protein is expressed in primary human breast tumors compared to normal breast tissue, and especially in triple-negative breast cancers (TNBC), which currently have no targeted therapies.
- High levels of ADAM8 expression predict poor breast cancer clinical outcome and are detected in half of patient metastases.
- ADAM8 promotes tumor growth and dissemination in an orthotopic mouse model by stimulating angiogenesis (via the release of VEGF-A and other pro-angiogenic growth factors) and tumor cell intra/extravasation (via activation of β1-integrin).
- Treatment of mice with a monoclonal antibody targeting ADAM8 extracellular domains initiated at the time of TNBC cell implantation in the mammary fat pad significantly reduces tumor growth, angiogenesis and metastasis.
- Treatment of pre-existing tumors with the ADAM8 antibody in a neoadjuvant setting profoundly reduces metastases in a mouse resection model, further validating ADAM8 as a therapeutic target of TNBC.