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ADAM10 releases a soluble form of the GPNMB/Osteoactivin extracellular domain with angiogenic properties.

ABSTRACT: Glycoprotein non-metastatic melanoma protein B (GPNMB)/Osteoactivin (OA) is a transmembrane protein expressed in approximately 40-75% of breast cancers. GPNMB/OA promotes the migration, invasion and metastasis of breast cancer cells; it is commonly expressed in basal/triple-negative breast tumors and is associated with shorter recurrence-free and overall survival times in patients with breast cancer. Thus, GPNMB/OA represents an attractive target for therapeutic intervention in breast cancer; however, little is known about the functions of GPNMB/OA within the primary tumor microenvironment.We have employed mouse and human breast cancer cells to investigate the effects of GPNMB/OA on tumor growth and angiogenesis. GPNMB/OA-expressing tumors display elevated endothelial recruitment and reduced apoptosis when compared to vector control-derived tumors. Primary human breast cancers characterized by high vascular density also display elevated levels of GPNMB/OA when compared to those with low vascular density. Using immunoblot and ELISA assays, we demonstrate the GPNMB/OA ectodomain is shed from the surface of breast cancer cells. Transient siRNA-mediated knockdown studies of known sheddases identified ADAM10 as the protease responsible for GPNMB/OA processing. Finally, we demonstrate that the shed extracellular domain (ECD) of GPNMB/OA can promote endothelial migration in vitro.GPNMB/OA expression promotes tumor growth, which is associated with enhanced endothelial recruitment. We identify ADAM10 as a sheddase capable of releasing the GPNMB/OA ectodomain from the surface of breast cancer cells, which induces endothelial cell migration. Thus, ectodomain shedding may serve as a novel mechanism by which GPNMB/OA promotes angiogenesis in breast cancer.

SUBMITTER: Rose AA

PROVIDER: S-EPMC2919417 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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ADAM10 releases a soluble form of the GPNMB/Osteoactivin extracellular domain with angiogenic properties.

Rose April A N AA Annis Matthew G MG Dong Zhifeng Z Pepin Francois F Hallett Michael M Park Morag M Siegel Peter M PM

PloS one 20100810 8

<h4>Background</h4>Glycoprotein non-metastatic melanoma protein B (GPNMB)/Osteoactivin (OA) is a transmembrane protein expressed in approximately 40-75% of breast cancers. GPNMB/OA promotes the migration, invasion and metastasis of breast cancer cells; it is commonly expressed in basal/triple-negative breast tumors and is associated with shorter recurrence-free and overall survival times in patients with breast cancer. Thus, GPNMB/OA represents an attractive target for therapeutic intervention i ...[more]

PMID: 20711474

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Dataset Information

ADAM10 releases a soluble form of the GPNMB/Osteoactivin extracellular domain with angiogenic properties.

Publications

ADAM10 releases a soluble form of the GPNMB/Osteoactivin extracellular domain with angiogenic properties.

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