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  • br Southern University of Science and Technology Shenzhen Gu

    2020-03-17


    4Southern University of Science and Technology, Shenzhen, Guangdong 518055, China 5Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA
    6Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA 7Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA 8Computational Structural Biology Section, Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA
    9Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel 10Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA 11Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA 12Lead Contact *Correspondence: [email protected] (J.F.), [email protected] (W.L.), [email protected] (F.C.)
    SUMMARY
    Triple-negative breast cancer (TNBC) is an aggres-sive and heterogeneous disease that lacks clinically actionable genetic alterations that limit targeted therapies. Here we explore a systems pharma-cology approach that integrates drug-target net-works and large-scale genomic profiles of TNBC and identify wogonoside, one of the major active flavonoids, as a potent angiogenesis inhibitor. We validate that wogonoside attenuates cell migra-tion, tube formation, and rat CY7-SE microvessel outgrowth, and reduces formation of blood vessels in chicken chorioallantoic membrane and TNBC cell-induced Matrigel plugs. In addition, wogono-side inhibits growth and angiogenesis in TNBC cell xenograft models. This network-based approach predicts, and we empirically validate, wogonoside’s antiangiogenic effects resulting from vascular endo-thelial growth factor secretion. Mechanistically, wo-gonoside inhibits Gli1 nuclear translocation and transcriptional activities associated with Hedgehog signaling, by promoting Smoothened degradation in a proteasome-dependent mechanism. This study offers a powerful, integrated, systems pharma-cology-based strategy for oncological drug discov-ery and identifies wogonoside as a potential TNBC angiogenesis inhibitor. 
    INTRODUCTION
    Triple-negative breast cancer (TNBC), characterized by absence or minimal expression of estrogen receptor, progester-one receptor, and human epidermal growth factor receptor 2 (HER2), is an aggressive and heterogeneous subtype that con-stitutes 15%–20% of patients with breast cancer (Penault-Llorca and Viale, 2012). The development of targeted therapies for TNBC has been challenging owing to the unexpected genomic heterogeneity and lack of consistently recurrent ge-netic alterations (Bareche et al., 2018; Bianchini et al., 2016). Neoadjuvant chemotherapy including a combination of taxanes (mitotic inhibitors) and anthracyclines (DNA intercalators) re-mains standard of care in nonmetastatic TNBC, since neither endocrine therapies nor HER2-targeted agents are effective (Bianchini et al., 2016; Foulkes et al., 2010; Lehmann and Pie-tenpol, 2014). Although chemotherapy is only effective in a small population of patients with TNBC, long-term survival is poor due to high rate of relapse and 30%–50% of patients acquiring resis-tance (Foulkes et al., 2010). Therefore, there is an urgent need for effective therapeutic strategies for TNBC, ones which sur-mount the genomic heterogeneity of patients with TNBC (Cheng et al., 2019b).
    Angiogenesis is an essential step for tumor development, which is principally initiated by chemoattractant and prolifera-tive cytokines such as vascular endothelial growth factor (VEGF) (Carmeliet and Jain, 2011). Previous studies have shown that TNBC possesses high microvessel density (Mohammed et al., 2011) and VEGF amplification compared with non-TNBC (Andre et al., 2009), such that patients with TNBC have