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

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