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
Menée sur 152 patientes atteintes d'un cancer du sein et sur 1 881 autres patientes, cette étude montre que, contrairement au facteur tissulaire (facteur impliqué dans le processus de coagulation), l'expression tumorale, les niveaux plasmatiques et les variants génétiques des inhibiteurs de la voie du facteur tissulaire (TFPI-alpha et TFPI-bêta) sont associés aux caractéristiques clinicopathologiques de la maladie ou à la survie des patientes
Introduction : Hypercoagulability in malignancy is known to increase 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 (alpha and beta), 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 TFPIalpha and TFPIbeta 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 (alpha+beta) (P=0.021) and TFPIbeta (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 TFPIalpha and TFPIbeta 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 TFPIalpha and TFPIbeta, 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.
Breast Cancer Research , article en libre accès, 2014