title: Not all NOTCH Is Created Equal: The Oncogenic Role of NOTCH2 in Bladder Cancer and Its Implications for Targeted Therapy.
abstract: Recent molecular analyses of bladder cancer open the door to significant advances in targeted therapies. NOTCH has been identified as a tumor suppressor in bladder cancer, but prior reports have focused on NOTCH1 Here we hypothesized that NOTCH2 is an oncogene suitable for therapeutic targeting in bladder cancer.
  
  
  
  We studied genomic aberrations of NOTCH, compared survival and tumor progression according to NOTCH2 expression levels, and studied NOTCH2 function in vitro and vivo
  
  
  
  We report a high rate of NOTCH2 copy number gain in bladder cancer. High NOTCH2 expression was identified especially in the basal subtype and in mesenchymal tumors. NOTCH2 activation correlated with adverse disease parameters and worse prognosis by immunohistochemistry. Forced overexpression of the intracellular domain of NOTCH2 (N2ICD) induced cell growth and invasion by cell-cycle progression, maintenance of stemness and epithelial-to-mesenchymal transition (EMT). These effects were abrogated by silencing of CSL, indicating that the effects were mediated through the canonical NOTCH signaling pathway. In an orthotopic xenograft model, forced overexpression of N2ICD increased growth, invasion, and metastasis. To explore the potential for therapeutic targeting of NOTCH2, we first silenced the receptor with shRNA and subsequently treated with a specific inhibitory antibody. Both interventions decreased cell growth, invasion, and metastasis in vitro and in the orthotopic xenograft model.
  
  
  
  We have demonstrated that NOTCH2 acts as an oncogene that promotes bladder cancer growth and metastasis through EMT, cell-cycle progression, and maintenance of stemness. Inhibition of NOTCH2 is a rational novel treatment strategy for invasive bladder cancer. Clin Cancer Res; 22(12); 2981-92. ©2016 AACR.
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada. Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada. Department of Urology, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.
authors.forename: Tetsutaro
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada. Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Kilian M
authors.initials: KM
authors.lastname: Gust
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada. Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Wyatt
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada. Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada. Department of Urology, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Goriki
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada. Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jäger
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada. Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Shannon
authors.initials: S
authors.lastname: Awrey
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada. Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada. Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Htoo Zarni
authors.initials: HZ
authors.lastname: Oo
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada. Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Manuel
authors.initials: M
authors.lastname: Altamirano-Dimas
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada. Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Ralph
authors.initials: R
authors.lastname: Buttyan
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada. Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.affiliation: Department of Urology, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Matsubara
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada. Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada. pblack@mail.ubc.ca.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Black
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D018628:Gene Dosage / Q000235:genetics; D006801:Humans; D008207:Lymphatic Metastasis / Q000235:genetics; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051881:Receptor, Notch1 / Q000096:biosynthesis; D051883:Receptor, Notch2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D000071656:Receptor, Notch3 / Q000096:biosynthesis; D015398:Signal Transduction / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C497761:NOTCH1 protein, human; C497764:NOTCH2 protein, human; C499374:NOTCH3 protein, human; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D000071656:Receptor, Notch3