Abstract
BackgroundGlycoprotein 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.Methodology/Principal FindingsWe 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.Conclusions/SignificanceGPNMB/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.
Highlights
Glycoprotein non-metastatic melanoma protein B (GPNMB) is a type I transmembrane protein that is known as Osteoactivin (OA), Dendritic Cell–Heparin Integrin Ligand (DC-HIL) or Hematopoietic Growth Factor Inducible Neurokinin-1 type (HGFIN)
We have reported that GPNMB/OA expression is increased in in vivo selected aggressively bone metastatic subpopulations of 4T1 mammary carcinoma cells [18]
In addition to bone metastatic sub-populations (592, 593), GPNMB/OA is overexpressed in 4T1 sub-populations that are either aggressively metastatic to lung (526), liver (2776, 2792) or that have been explanted from primary tumors (066) (Figure 1A)
Summary
Glycoprotein non-metastatic melanoma protein B (GPNMB) is a type I transmembrane protein that is known as Osteoactivin (OA), Dendritic Cell–Heparin Integrin Ligand (DC-HIL) or Hematopoietic Growth Factor Inducible Neurokinin-1 type (HGFIN). GPNMB/OA is expressed in a wide array of normal tissue types including: the bone, hematopoietic system and the skin. We showed that ectopic expression of GPNMB/OA in poorly metastatic 66cl mouse mammary carcinoma cells is sufficient to induce MMP-3 expression and increases their invasion in vitro and promotes bone metastasis in vivo [18]. 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. GPNMB/OA represents an attractive target for therapeutic intervention in breast cancer; little is known about the functions of GPNMB/OA within the primary tumor microenvironment
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