title: ZNF217 is a marker of poor prognosis in breast cancer that drives epithelial-mesenchymal transition and invasion.
abstract: The Krüppel-like zinc finger protein ZNF217 is a candidate oncogene in breast cancer. In this study, we showed that high levels of expression of ZNF217 mRNA are associated with poor prognosis and the development of metastases in breast cancer. Overexpression of ZNF217 in breast cancer cells stimulated migration and invasion in vitro and promoted the development of spontaneous lung or node metastases in mice in vivo. ZNF217 also promoted epithelial-mesenchymal transition (EMT) in human mammary epithelial cells, and the TGF-β-activated Smad signaling pathway was identified as a major driver of ZNF217-induced EMT. In addition, a TGF-β autocrine loop sustained activation of the TGF-β pathway in ZNF217-overexpressing mammary epithelial cells, most likely because of ZNF217-mediated direct upregulation of TGFB2 or TGFB3. Inhibition of the TGF-β pathway led to the reversal of ZNF217-mediated EMT. Together, our findings indicate that ZNF217 mRNA expression may represent a novel prognostic biomarker in breast cancer. Therapeutic targeting of ZNF217 of the TGF-β signaling pathway may benefit the subset of patients whose tumors express high levels of ZNF217.
authors.affiliation: ISPB, Faculté de Pharmacie, Université Lyon 1, Lyon, France.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Vendrell
authors.forename: Aurélie
authors.initials: A
authors.lastname: Thollet
authors.forename: Nhan T
authors.initials: NT
authors.lastname: Nguyen
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Ghayad
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Vinot
authors.forename: Ivan
authors.initials: I
authors.lastname: Bièche
authors.forename: Evelyne
authors.initials: E
authors.lastname: Grisard
authors.forename: Véronique
authors.initials: V
authors.lastname: Josserand
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Coll
authors.forename: Pierre
authors.initials: P
authors.lastname: Roux
authors.forename: Laura
authors.initials: L
authors.lastname: Corbo
authors.forename: Isabelle
authors.initials: I
authors.lastname: Treilleux
authors.forename: Ruth
authors.initials: R
authors.lastname: Rimokh
authors.forename: Pascale A
authors.initials: PA
authors.lastname: Cohen
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D008207:Lymphatic Metastasis; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics*; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D051785:Smad Proteins; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; C113698:ZNF217 protein, human