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

• Published in: Oncogene 2019-06, Vol.38 (26), p.5294-5307
• Main Authors: Maric, Gordana, Annis, Matthew G., MacDonald, Patricia A., Russo, Caterina, Perkins, Dru, Siwak, Doris R., Mills, Gordon B., Siegel, Peter M.
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/1; 13/106; 13/51; 13/95; 631/67/1347; 631/67/70; 64/110; 82/79; AKT protein; Animals; Apoptosis; beta Catenin - metabolism; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Biology; Cell Line, Tumor; Cell Proliferation - genetics; Cell Transformation, Neoplastic - genetics; Epithelium; Female; Gene Expression Regulation, Neoplastic; Growth rate; Human Genetics; Humans; Internal Medicine; Mammary gland; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; Medicine; Medicine & Public Health; Membrane Glycoproteins - physiology; Metastases; Mice; Mice, Transgenic; Molecular modelling; Oncology; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Signal transduction; TOR protein; TOR Serine-Threonine Kinases - metabolism; Transcription; Transgenic mice; Tumors; Up-Regulation - genetics; Wnt protein; Wnt Signaling Pathway - genetics; Wnt1 Protein - genetics; Wnt1 Protein - metabolism; β-Catenin
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-019-0793-7

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.