Abstract
Abstract Purpose: While the murine orthologue of GPNMB (Glycoprotein non-metastatic B, DC-HIL, HGFIN), Osteoactivin, has been shown to promote breast cancer metastasis in an in vivo mouse model, its importance in human breast cancer is unknown. We have examined the significance of GPNMB expression as a prognostic indicator of recurrence and assessed its potential as a novel therapeutic target in breast cancer. Experimental Design: The clinical significance of GPNMB expression in breast cancer was addressed by analyzing GPNMB mRNA levels in several published gene expression datasets and by determining GPNMB protein expression in two independent tissue microarrays derived from human breast tumors. Human breast cancer cell lines endogenously or exogenously expressing GPNMB were further used to validate a toxin-conjugated anti-GPNMB antibody as a novel therapeutic agent. Results: GPNMB expression correlates with shorter times to recurrence and reduced overall survival of breast cancer patients. Epithelial-specific staining of GPNMB serves as an independent prognostic indicator for breast cancer recurrence. GPNMB is highly expressed in basal and triple-negative (TN) breast cancers and is associated with increased risk of recurrence within this subtype. GPNMB expression confers a more migratory and invasive phenotype on breast cancer cells. Treatment of mice harbouring endogenous GPNMB-expressing human breast cancer xenografts with CDX-011 (glembatumumab vedotin, CR011-vcMMAE), a GPNMB-targeted antibody-drug conjugate, induces and sustains tumor regression in vivo. Conclusions: GPNMB expression is associated with the basal/TN subtype and is a prognostic marker of poor outcome in patients with breast cancer. CDX-011 (glembatumumab vedotin) is a promising new targeted therapy for patients with metastatic TN breast cancers, a patient population that currently lacks targeted-therapy options. Citation Information: Clin Cancer Res 2010;16(7 Suppl):A8
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