title: Notch3 overexpression promotes anoikis resistance in epithelial ovarian cancer via upregulation of COL4A2.
abstract: Ovarian cancer is a lethal disease with the majority of diagnosed women having distant metastases. Interestingly, although Notch3 overexpression has been correlated with poor survival in epithelial ovarian cancer (EOC), little is known about its mechanism of action. Data show that Notch3 specifically promotes anoikis resistance. In addition, data indicate a positive role for focal adhesion kinase (FAK) as well as downstream signaling kinases such as Akt and Erk 1/2 in promoting anchorage-independent growth. Mechanistically, both mRNA transcript and protein levels of type IV collagen (COL4A2) are reduced when Notch3 levels are decreased and exogenous collagen IV supplementation reverses the anoikis sensitivity. Reduction of COL4A2 expression by RNAI-mediated knockdown induces cell death. Finally, elevated Notch3 expression levels correlate with higher COL4A2 expression in human ovarian tumor specimens.
  
  
  CONCLUSIONS
  These data highlight type IV collagen as a novel therapeutic target for metastatic EOC. Visual Overview: http://mcr.aacrjournals.org/content/early/2014/11/25/1541-7786.MCR-14-0334/F1.large.jpg
authors.affiliation: Graduate Program in Pathobiology, Brown University, Providence, Rhode Island.
authors.forename: Caitlin W
authors.initials: CW
authors.lastname: Brown
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Brodsky
authors.affiliation: Graduate Program in Pathobiology, Brown University, Providence, Rhode Island. Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island. Richard_Freiman@Brown.edu.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Freiman
mesh_terms: D023102:Anoikis / Q000235:genetics*; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D024141:Collagen Type IV / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D009362:Neoplasm Metastasis; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C502625:COL4A2 protein, human; D024141:Collagen Type IV; C499374:NOTCH3 protein, human; D012333:RNA, Messenger; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D051416:Focal Adhesion Protein-Tyrosine Kinases