Glycoprotein nmb (GPNMB) promotes
breast tumor growth and
metastasis and its expression in
tumor epithelium correlates with poor prognosis in
breast cancer patients. Despite its
biological and clinical significance, little is known regarding the molecular mechanisms engaged by GPNMB. Herein, we show that GPNMB engages distinct functional domains and mechanisms to promote primary
tumor growth and
metastasis. We demonstrate that
neuropilin-1 (NRP-1) expression is increased in
breast cancer cells that overexpress GPNMB. Interestingly, the GPNMB-driven increase in NRP-1 expression potentiated
vascular endothelial growth factor signaling in
breast cancer cells and was required for the growth, but not
metastasis, of these cells in vivo. Interrogation of RNAseq data sets revealed a positive correlation between GPNMB and NRP-1 levels in human
breast tumors. Furthermore, we ascribe pro-growth and pro-metastatic functions of GPNMB to its ability to bind α5β1
integrin and increase downstream signaling in
breast cancer cells. We show that GPNMB enhances
breast cancer cell adhesion to
fibronectin, increases α5β1 expression and associates with this receptor through its RGD motif. GPNMB recruitment into
integrin complexes activates Src and Fak signaling pathways in an RGD-dependent manner. Importantly, both the RGD motif and cytoplasmic tail of GPNMB are required to promote primary mammary
tumor growth; however, only mutation of the RGD motif impaired the formation of lung
metastases. Together, these findings identify novel and distinct molecular mediators of GPNMB-induced
breast cancer growth and
metastasis.