title: The matricellular protein CCN6 (WISP3) decreases Notch1 and suppresses breast cancer initiating cells.
abstract: Increasing evidence supports that the epithelial to mesenchymal transition (EMT) in breast cancer cells generates tumor initiating cells (TICs) but the contribution of the tumor microenvironment to these programs needs further elucidation. CCN6 (WISP3) is a secreted matrix-associated protein (36.9 kDa) of the CCN family (named after CTGF, Cyr61 and Nov) that is reduced or lost in invasive carcinomas of the breast with lymph node metastasis and in inflammatory breast cancer. CCN6 exerts breast cancer growth and invasion inhibitory functions, but the mechanisms remain to be defined. In the present study we discovered that ectopic CCN6 overexpression in triple negative (TN) breast cancer cells and in cells derived from patients is sufficient to induce a mesenchymal to epithelial transition (MET) and to reduce TICs. In vivo, CCN6 overexpression in the TIC population of MDA-MB-231 cells delayed tumor initiation, reduced tumor volume, and inhibited the development of metastasis. Our studies reveal a novel CCN6/Slug signaling axis that regulates Notch1 signaling activation, epithelial cell phenotype and breast TICs, which requires the conserved thrombospondin type 1 (TSP1) motif of CCN6. The relevance of these data to human breast cancer is highlighted by the finding that CCN6 protein levels are inversely correlated with Notch1 intracellular activated form (NICD1) in 69.5% of invasive breast carcinomas. These results demonstrate that CCN6 regulates epithelial and mesenchymal states transition and TIC programs, and pinpoint one responsible mechanism.
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Martin
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Boris
authors.initials: B
authors.lastname: Burman
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Gonzalez
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Celina G
authors.initials: CG
authors.lastname: Kleer
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D055511:CCN Intercellular Signaling Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D005260:Female; D064593:Heterografts; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D051881:Receptor, Notch1 / Q000096:biosynthesis*; D059016:Tumor Microenvironment / Q000502:physiology
chemical_list: D055511:CCN Intercellular Signaling Proteins; C400081:CCN6 protein, human; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1
keywords: CCN6; WISP3; breast cancer; epithelial to mesenchymal transition; triple negative