title: Alternatively spliced tissue factor synergizes with the estrogen receptor pathway in promoting breast cancer progression.
abstract: BACKGROUND
  Procoagulant full-length tissue factor (flTF) and its minimally coagulant alternatively spliced isoform (asTF), promote breast cancer (BrCa) progression via different mechanisms. We previously showed that flTF and asTF are expressed by BrCa cells, resulting in autoregulation in a cancer milieu. BrCa cells often express hormone receptors such as the estrogen receptor (ER), leading to the formation of hormone-regulated cell populations.
  
  
  OBJECTIVE
  To investigate whether TF isoform-specific and ER-dependent pathways interact in BrCa.
  
  
  METHODS
  Tissue factor isoform-regulated gene sets were assessed using ingenuity pathway analysis. Tissues from a cohort of BrCa patients were divided into ER-positive and ER-negative groups. Associations between TF isoform levels and tumor characteristics were analyzed in these groups. BrCa cells expressing TF isoforms were assessed for proliferation, migration and in vivo growth in the presence or absence of estradiol.
  
  
  RESULTS
  Ingenuity pathway analysis pointed to similarities between ER- and TF-induced gene expression profiles. In BrCa tissue specimens, asTF expression was associated with grade and stage in ER-positive but not in ER-negative tumors. flTF was only associated with grade in ER-positive tumors. In MCF-7 cells, asTF accelerated proliferation in the presence of estradiol in a β1 integrin-dependent manner. No synergy between asTF and the ER pathway was observed in a migration assay. Estradiol accelerated the growth of asTF-expressing tumors but not control tumors in vivo in an orthotopic setting.
  
  
  CONCLUSIONS
  Tissue factor isoform and estrogen signaling share downstream targets in BrCa; the concomitant presence of asTF and estrogen signaling is required to promote BrCa cell proliferation.
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Kocatürk
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Tieken
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: Vreeken
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Ünlü
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: C C
authors.initials: CC
authors.lastname: Engels
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: E M
authors.initials: EM
authors.lastname: de Kruijf
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: P J
authors.initials: PJ
authors.lastname: Kuppen
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: P H
authors.initials: PH
authors.lastname: Reitsma
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: V Y
authors.initials: VY
authors.lastname: Bogdanov
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: H H
authors.initials: HH
authors.lastname: Versteeg
mesh_terms: D017398:Alternative Splicing; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018450:Disease Progression; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D019012:Integrin beta1 / Q000502:physiology; D060787:Neoplasm Grading; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D009367:Neoplasm Staging; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D011960:Receptors, Estrogen / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D012984:Software; D013925:Thromboplastin / Q000235:genetics / Q000502:physiology*; D046888:Tissue Array Analysis
chemical_list: D004967:Estrogens; D019012:Integrin beta1; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D011960:Receptors, Estrogen; D004958:Estradiol; D013925:Thromboplastin
keywords: blood coagulation; cell movement; cell proliferation; integrin beta1; tumors