title: GPNMB cooperates with neuropilin-1 to promote mammary tumor growth and engages integrin α5β1 for efficient breast cancer metastasis.
abstract: 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.
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Quebec, Canada.|Department of Medicine, McGill University, Montréal, Quebec, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Maric
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Quebec, Canada.|Department of Medicine, McGill University, Montréal, Quebec, Canada.
authors.forename: M G
authors.initials: MG
authors.lastname: Annis
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Quebec, Canada.|Department of Medicine, McGill University, Montréal, Quebec, Canada.
authors.forename: Z
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Quebec, Canada.|Department of Medicine, McGill University, Montréal, Quebec, Canada.
authors.forename: A A N
authors.initials: AA
authors.lastname: Rose
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Quebec, Canada.|Department of Anatomy and Cell Biology, McGill University, Montréal, Quebec, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Ng
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Quebec, Canada.|Department of Anatomy and Cell Biology, McGill University, Montréal, Quebec, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Perkins
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Quebec, Canada.|Department of Medicine, McGill University, Montréal, Quebec, Canada.
authors.forename: P A
authors.initials: PA
authors.lastname: MacDonald
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Quebec, Canada.|Department of Medicine, McGill University, Montréal, Quebec, Canada.
authors.forename: V
authors.initials: V
authors.lastname: Ouellet
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Quebec, Canada.|Department of Medicine, McGill University, Montréal, Quebec, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Russo
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Quebec, Canada.|Department of Medicine, McGill University, Montréal, Quebec, Canada.|Department of Anatomy and Cell Biology, McGill University, Montréal, Quebec, Canada.|Department of Biochemistry, McGill University, Montréal, Quebec, Canada.
authors.forename: P M
authors.initials: PM
authors.lastname: Siegel
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics*; D005260:Female; D005353:Fibronectins / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D039081:Integrin alpha5beta1 / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology; D039942:Neuropilin-1 / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D005353:Fibronectins; C503042:GPNMB protein, human; D039081:Integrin alpha5beta1; D008562:Membrane Glycoproteins; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1