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GPNMB cooperates with neuropilin-1 to promote mammary tumor growth and engages integrin α5β1 for efficient breast cancer metastasis

Oncogene volume 34, pages 5494–5504 (2015)Cite this article

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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.

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Acknowledgements

We thank members of the Siegel laboratory for their thoughtful discussions regarding the current work and are also grateful to Dr Josie Ursini-Siegel for her critical reading of the manuscript. We acknowledge the Goodman Cancer Research Centre histology core facility (McGill University) for routine histological services. GM acknowledges studentship support from the Canadian Institutes for Health Research (CIHR). PMS was supported by the Fonds de recherche en santé du Québec (FRSQ) research scholar program (Junior 2) and is currently a McGill University William Dawson Scholar. This research was supported solely by a grant from the CIHR (MOP-119401).

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Authors and Affiliations

  1. Goodman Cancer Research Centre, McGill University, Montréal, Quebec, Canada

    G Maric, M G Annis, Z Dong, A A N Rose, S Ng, D Perkins, P A MacDonald, V Ouellet, C Russo & P M Siegel

  2. Department of Medicine, McGill University, Montréal, Quebec, Canada

    G Maric, M G Annis, Z Dong, A A N Rose, P A MacDonald, V Ouellet, C Russo & P M Siegel

  3. Department of Anatomy and Cell Biology, McGill University, Montréal, Quebec, Canada

    S Ng, D Perkins & P M Siegel

  4. Department of Biochemistry, McGill University, Montréal, Quebec, Canada

    P M Siegel

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Maric, G., Annis, M., Dong, Z. et al. GPNMB cooperates with neuropilin-1 to promote mammary tumor growth and engages integrin α5β1 for efficient breast cancer metastasis. Oncogene 34, 5494–5504 (2015). https://doi.org/10.1038/onc.2015.8

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