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GPNMB augments Wnt-1 mediated breast tumor initiation and growth by enhancing PI3K/AKT/mTOR pathway signaling and β-catenin activity

Oncogene volume 38, pages 5294–5307 (2019)Cite this article

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Abstract

Glycoprotein Nmb (GPNMB) is overexpressed in triple-negative and basal-like breast cancers and its expression is predictive of poor prognosis within this aggressive breast cancer subtype. GPNMB promotes breast cancer growth, invasion, and metastasis; however, its role in mammary tumor initiation remains unknown. To address this question, we overexpressed GPNMB in the mammary epithelium to generate MMTV/GPNMB transgenic mice and crossed these animals to the MMTV/Wnt-1 mouse model, which is known to recapitulate features of human basal breast cancers. We show that GPNMB alone does not display oncogenic properties; however, its expression dramatically accelerates tumor onset in MMTV/Wnt-1 mice. MMTV/Wnt-1 × MMTV/GPNMB bigenic mice also exhibit a significant increase in the growth rate of established primary tumors, which is attributable to increased proliferation and decreased apoptosis. To elucidate molecular mechanisms underpinning the tumor-promoting effects of GPNMB in this context, we interrogated activated pathways in tumors derived from the MMTV/Wnt-1 and MMTV/Wnt-1 × MMTV/GPNMB mice using RPPA analysis. These data revealed that MMTV/Wnt-1 × MMTV/GPNMB bigenic tumors exhibit a pro-growth signature characterized by elevated PI3K/AKT/mTOR signaling and increased β-catenin activity. Furthermore, we extended these observations to an independent Wnt-1 expressing model of aggressive breast cancer, and confirmed that GPNMB enhances canonical Wnt pathway activation, as evidenced by increased β-catenin transcriptional activity, in breast cancer cells and tumors co-expressing Wnt-1 and GPNMB. GPNMB-dependent engagement of β-catenin occurred, in part, through AKT activation. Taken together, these data ascribe a novel, pro-growth role for GPNMB in Wnt-1 expressing basal breast cancers.

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Acknowledgements

We acknowledge the Goodman Cancer Research Centre (GCRC) transgenic facility (McGill University) for generation of the MMTV/GPNMB mice, the GCRC histology core facility (McGill University) for routine histological services and Zhifeng Dong for some Immunohistochemical staining. We thank members of the Siegel laboratory for thoughtful discussions and critical reading of the manuscript. GM acknowledges studentship support from the Canadian Institutes for Health Research (CIHR). PMS is currently a McGill University William Dawson Scholar. This research was supported solely by grants from the CIHR (MOP-119401; PJT-153327).

Author contributions

GM, MGA, and PMS designed research; GM and MGA performed experiments; PM, CR, MGA, and DP generated reagents used in this study; DRS and GM performed and analyzed the RPPA analysis; GM, MGA, and PMS analyzed/interpreted data and GM, MGA, and PMS wrote the manuscript.

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  1. These authors contributed equally: Gordana Maric, Matthew G. Annis

Authors and Affiliations

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

    Gordana Maric, Matthew G. Annis, Patricia A. MacDonald, Caterina Russo, Dru Perkins & Peter M. Siegel

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

    Gordana Maric, Matthew G. Annis, Patricia A. MacDonald, Caterina Russo & Peter M. Siegel

  3. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Doris R. Siwak

  4. Department of Cell, Development and Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97201, USA

    Gordon B. Mills

  5. Department of Biochemistry, McGill University, Montréal, Québec, Canada

    Peter M. Siegel

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Supplmental Materials

41388_2019_793_MOESM2_ESM.pptx

Supplementary Figure 1. MMTV/GPNMB transgenic mice express GPNMB in the mammary ductal epithelium and display normal virgin mammary gland development

Supplementary Figure 2. Tumor incidence in virgin and multiparous MMTV/GPNMB Mice

Supplementary Figure 3. Immunohistochemistry and Immunoblots of MMTV/Wnt-1 and MMTV/Wnt-1 x MMTV/GPNMB tumors

41388_2019_793_MOESM5_ESM.pptx

Supplementary Figure 4. Immunohistochemistry of MMTV/Wnt-1 and MMTV/Wnt-1 x MMTV/GPNMB tumors to validate targets of the mTOR pathway

41388_2019_793_MOESM6_ESM.pptx

Supplementary Figure 5. Immunoblot analysis of epithelial and mesenchymal markers in 4T1-533LM and transgenic derived mammary tumors

Supplementary Table 1: Raw RPPA data

Supplementary Table 2: Targets significantly up- or down- regulated by GPNMB expression

Supplementary Table 3: A list of oligonucleotide sequences used in the current study

Supplementary Table 4: A list of antibodies used in the current study

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Maric, G., Annis, M.G., MacDonald, P.A. et al. GPNMB augments Wnt-1 mediated breast tumor initiation and growth by enhancing PI3K/AKT/mTOR pathway signaling and β-catenin activity. Oncogene 38, 5294–5307 (2019). https://doi.org/10.1038/s41388-019-0793-7

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