title: Tumor expression, plasma levels and genetic polymorphisms of the coagulation inhibitor TFPI are associated with clinicopathological parameters and survival in breast cancer, in contrast to the coagulation initiator TF.
abstract: BACKGROUND
  Hypercoagulability in malignancy increases the risk of thrombosis, but is also involved in cancer progression. Experimental studies suggest that tissue factor (TF) and tissue factor pathway inhibitor (TFPI) are involved in cancer biology as a tumor- promoter and suppressor, respectively, but the clinical significance is less clear. Here, we aimed to investigate the clinical relevance of TF and TFPI genetic and phenotypic diversity in breast cancer.
  
  
  METHODS
  The relationship between tumor messenger RNA (mRNA) expression and plasma levels of TF and TFPI (α and β), tagging single nucleotide polymorphisms (tagSNPs) in F3 (TF) (n=6) and TFPI (n=18), and clinicopathological characteristics and molecular tumor subtypes were explored in 152 treatment naive breast cancer patients. The effect of tumor expressed TF and TFPIα and TFPIβ on survival was investigated in a merged breast cancer dataset of 1881 patients.
  
  
  RESULTS
  Progesterone receptor negative patients had higher mRNA expression of total TFPI (α+β) (P=0.021) and TFPIβ (P=0.014) in tumors. TF mRNA expression was decreased in grade 3 tumors (P=0.003). In plasma, total TFPI levels were decreased in patients with larger tumors (P=0.013). SNP haplotypes of TFPI, but not TF, were associated with specific clinicopathological characteristics like tumor size (odds ratio (OR) 3.14, P=0.004), triple negativity (OR 2.4, P=0.004), lymph node spread (OR 3.34, P=0.006), and basal-like (OR 2.3, P=0.011) and luminal B (OR 3.5, P=0.005) molecular tumor subtypes. Increased expression levels of TFPIα and TFPIβ in breast tumors were associated with better outcome in all tumor subtypes combined (P=0.007 and P=0.005) and in multiple subgroups, including lymph node positive subjects (P=0.006 and P=0.034).
  
  
  CONCLUSIONS
  This study indicates that genetic and phenotypic variation of both TFPIα and TFPIβ, more than TF, are markers of cancer progression. Together with the previously demonstrated tumor suppressor effects of TFPI, the beneficial effect of tumor expressed TFPI on survival, renders TFPI as a potential anticancer agent, and the clinical significance of TFPI in cancer deserves further investigation.
authors.affiliation: Department of Medical Genetics, Oslo University Hospital and University of Oslo, BOX 4956, Nydalen, Oslo, N-0424, Norway. mari.tinholt@medisin.uio.no.|Department of Haematology and Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway. mari.tinholt@medisin.uio.no.|Institute of Clinical Medicine, University of Oslo, Oslo, Norway. mari.tinholt@medisin.uio.no.
authors.forename: Mari
authors.initials: M
authors.lastname: Tinholt
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway. hans.kristian.vollan@me.com.|The K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. hans.kristian.vollan@me.com.|Department of Oncology, Division of Surgery, Transplantation and Cancer Medicine, Oslo University Hospital Radiumhospitalet, Oslo, Norway. hans.kristian.vollan@me.com.
authors.forename: Hans Kristian Moen
authors.initials: HK
authors.lastname: Vollan
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway. kristine.kleivi@gmail.com.|The K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. kristine.kleivi@gmail.com.|Department of Research, Vestre Viken, Drammen, Norway. kristine.kleivi@gmail.com.
authors.forename: Kristine Kleivi
authors.initials: KK
authors.lastname: Sahlberg
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway. Sandra.Nyberg@rr-research.no.
authors.forename: Sandra
authors.initials: S
authors.lastname: Jernström
authors.affiliation: Department of Medical Genetics, Oslo University Hospital and University of Oslo, BOX 4956, Nydalen, Oslo, N-0424, Norway. fatemeh.kaveh@medisin.uio.no.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Kaveh
authors.affiliation: The K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. ole@ifi.uio.no.|Biomedical Informatics Research Group, Department of Informatics, University of Oslo, Oslo, Norway. ole@ifi.uio.no.
authors.forename: Ole Christian
authors.initials: OC
authors.lastname: Lingjærde
authors.affiliation: Institute of Clinical Medicine, University of Oslo, Oslo, Norway. rolf.karesen@medisin.uio.no.|The K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. rolf.karesen@medisin.uio.no.|Department of Breast and Endocrine Surgery, Oslo University Hospital, Oslo, Norway. rolf.karesen@medisin.uio.no.
authors.forename: Rolf
authors.initials: R
authors.lastname: Kåresen
authors.affiliation: Department of Pathology, Akershus University Hospital, Lørenskog, Norway. torill.sauer@medisin.uio.no.
authors.forename: Torill
authors.initials: T
authors.lastname: Sauer
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway. v.n.kristensen@medisin.uio.no.|The K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. v.n.kristensen@medisin.uio.no.|Department of Clinical Molecular Biology (EpiGen), Akershus University Hospital, Lørenskog, Norway. v.n.kristensen@medisin.uio.no.
authors.forename: Vessela
authors.initials: V
authors.lastname: Kristensen
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway. a.l.borresen-dale@medisin.uio.no.|The K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. a.l.borresen-dale@medisin.uio.no.
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.affiliation: Department of Haematology and Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway. p.m.sandset@medisin.uio.no.|Institute of Clinical Medicine, University of Oslo, Oslo, Norway. p.m.sandset@medisin.uio.no.
authors.forename: Per Morten
authors.initials: PM
authors.lastname: Sandset
authors.affiliation: Department of Medical Genetics, Oslo University Hospital and University of Oslo, BOX 4956, Nydalen, Oslo, N-0424, Norway. nina.iversen@medisin.uio.no.
authors.forename: Nina
authors.initials: N
authors.lastname: Iversen
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008074:Lipoproteins / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden
chemical_list: D014408:Biomarkers, Tumor; D008074:Lipoproteins; D012333:RNA, Messenger; C051928:lipoprotein-associated coagulation inhibitor; D013925:Thromboplastin