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

IntroductionHypercoagulability 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.MethodsThe 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.ResultsProgesterone 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).ConclusionsThis 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0548-5) contains supplementary material, which is available to authorized users.

Subtype‐specific clinical and prognostic relevance of tumor‐expressed F5 and regulatory F5 variants in breast cancer: the CoCaV study

“…The 503 patients had only tumor samples ( n = 142), only blood samples ( n = 213) or both blood and tumor samples available ( n = 148). The following clinicopathological characteristics were included in the study: tumor size, lymph node status, tumor grade, estrogen receptor (ER) status, progesterone receptor (PR) status and human epidermal growth factor receptor 2 (HER2) status (Table S1), as previously described . The prediction analysis of microarray 50 (PAM50) subtype algorithm was used to assign a subtype label to each sample, as described previously .…”

“…The following clinicopathological characteristics were included in the study: tumor size, lymph node status, tumor grade, estrogen receptor (ER) status, progesterone receptor (PR) status and human epidermal growth factor receptor 2 (HER2) status (Table S1), as previously described . The prediction analysis of microarray 50 (PAM50) subtype algorithm was used to assign a subtype label to each sample, as described previously . The Norwegian southeastern Regional Committee for Medical and Health Research Ethics approved the study protocols (approval number 1.2007.1125 for Ullevål patients and 429‐04148 for Akershus patients).…”

“…Cancer favors coagulation activation and increasing evidence suggests that the resulting procoagulant state actively supports the pathogenic mechanisms in cancer. The activation of the coagulation system is partly directed by the oncogene‐driven tumor expression of coagulation factors such as tissue factor (TF), factor (F) VII and FX . The ectopic expression of coagulation factors by tumor cells has been shown to support crucial cancer processes such as angiogenesis, metastasis and immune evasion, either in a coagulation‐dependent or independent manner via protease activated receptors (PARs) .…”

Targeting clotting proteins in cancer therapy – progress and challenges

“…In addition to the demonstrated role of the anticoagulant protein C (PC) pathway in controlling intravascular tumor dissemination (13;36-39), endothelial TF pathway inhibitor (TFPI) expression limits TF-dependent experimental metastasis (40). Tumor cell expression of TFPI is regulated by hypoxia inducible factor (HIF) 1α (41) and TFPI expression by tumor cells is correlated with improved outcome in breast cancer (42). Genetic polymorphisms associated with breast cancer furthermore show that traditional prothrombotic risk factors are not the sole determinant for tumor progression and that additional hemostatic components, i.e.…”

Integrated bioinformatics analysis and screening hub genes in papillary thyroid cancer

“…miR-500 inhibition could surpress the proliferation and invasion prostate cancer cell and tumorigenicity in vivo, while TFPI knockdown reversed the effects [26]. The level of TFPI in luminal-A breast cancer patients is signi cantly lower than healthy volunteers [27]. ZARYCHTA et al claimed that TF seemed to be a tumor-promoting factor while TFPI exerted tumor suppressor properties [28].…”