title: Downregulation of TFPI in breast cancer cells induces tyrosine phosphorylation signaling and increases metastatic growth by stimulating cell motility.
abstract: BACKGROUND
  Increased hemostatic activity is common in many cancer types and often causes additional complications and even death. Circumstantial evidence suggests that tissue factor pathway inhibitor-1 (TFPI) plays a role in cancer development. We recently reported that downregulation of TFPI inhibited apoptosis in a breast cancer cell line. In this study, we investigated the effects of TFPI on self-sustained growth and motility of these cells, and of another invasive breast cancer cell type (MDA-MB-231).
  
  
  METHODS
  Stable cell lines with TFPI (both α and β) and only TFPIβ downregulated were created using RNA interference technology. We investigated the ability of the transduced cells to grow, when seeded at low densities, and to form colonies, along with metastatic characteristics such as adhesion, migration and invasion.
  
  
  RESULTS
  Downregulation of TFPI was associated with increased self-sustained cell growth. An increase in cell attachment and spreading was observed to collagen type I, together with elevated levels of integrin α2. Downregulation of TFPI also stimulated migration and invasion of cells, and elevated MMP activity was involved in the increased invasion observed. Surprisingly, equivalent results were observed when TFPIβ was downregulated, revealing a novel function of this isoform in cancer metastasis.
  
  
  CONCLUSIONS
  Our results suggest an anti-metastatic effect of TFPI and may provide a novel therapeutic approach in cancer.
authors.affiliation: Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors.forename: Benedicte
authors.initials: B
authors.lastname: Stavik
authors.forename: Grethe
authors.initials: G
authors.lastname: Skretting
authors.forename: Hans-Christian
authors.initials: HC
authors.lastname: Aasheim
authors.forename: Mari
authors.initials: M
authors.lastname: Tinholt
authors.forename: Lillian
authors.initials: L
authors.lastname: Zernichow
authors.forename: Marit
authors.initials: M
authors.lastname: Sletten
authors.forename: Per Morten
authors.initials: PM
authors.lastname: Sandset
authors.forename: Nina
authors.initials: N
authors.lastname: Iversen
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D024042:Collagen Type I / Q000378:metabolism; D015536:Down-Regulation; D004318:Doxycycline / Q000031:analogs & derivatives; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039421:Integrin alpha2 / Q000378:metabolism; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D010960:Plasminogen Activators / Q000378:metabolism; D020033:Protein Isoforms; D034622:RNA Interference; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D024042:Collagen Type I; D039421:Integrin alpha2; D008074:Lipoproteins; D020033:Protein Isoforms; C051928:lipoprotein-associated coagulation inhibitor; D014443:Tyrosine; D010960:Plasminogen Activators; D020782:Matrix Metalloproteinases; D004318:Doxycycline