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Cancer Med. 2020 Jan 21. doi: 10.1002/cam4.2748. [Epub ahead of print]

Breast cancer stromal clotting activation (Tissue Factor and thrombin): A pre-invasive phenomena that is prognostic in invasion.

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Faculty of Biology, Medicine and Health, Division of Cancer Sciences, School of Medical Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester, UK.
Department of Pathology, Institute for Biomedicine, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.
Department of Histopathology, Manchester University NHS Foundation Trust, Wythenshawe, Manchester, UK.
Department of Histopathology, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK.
Department of Histopathology, East Lancashire Hospitals NHS Trust, Blackburn, UK.
The Nightingale Centre and Prevent Breast Cancer Research Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK.



Tumor stroma, of which fibroblasts are the most abundant cell, resembles a non-healing wound, where a procoagulant environment creates a permissive milieu for cancer growth. We aimed to determine if tumor expression of coagulation factors (procoagulant phenotype), and systemic hypercoagulability, occur at the preinvasive (ductal carcinoma in situ; DCIS) stage and correlate with breast cancer subtype, disease-free survival (DFS), and overall survival (OS).


In a prospective cohort of early breast cancer (DCIS, n = 76; invasive, n = 248) tumor, normal breast and plasma were examined. Fibroblast and epithelial expression of Tissue Factor (TF), thrombin, PAR1, PAR2, and plasma thrombin-antithrombin (TAT) and D-dimer were correlated with clinicopathological data, and 5-year survival.


Fibroblast expression of TF, thrombin, and PAR1 was increased in DCIS and invasive cancer compared to normal breast fibroblasts (P ≤ .003, all). Fibroblast TF, thrombin, PAR1, and PAR2 was increased in cancers with high Ki67, high grade, ER- (vs ER+), and HER2+ (vs HER2-) (all P < .05). On univariate analysis, fibroblast TF expression was inversely associated with DFS (P = .04) and OS (P = .02). D-dimer was higher in node positive (507 (CI: 411-625) ng/mL, n = 68) vs negative patients (428 (CI: 387-472) ng/mL, n = 171, P = .004) and inversely associated with OS (P = .047). On multivariate analysis, plasma TAT was associated with reduced OS (HR 3.26, CI 1.16-3.1, P = .02), with a high plasma TAT (≥3.2 ng/mL) associated with > 3-fold mortality risk compared to low TAT.


This demonstrates procoagulant phenotypic changes occur in fibroblasts at the preinvasive stage. Fibroblast procoagulant phenotype is associated with aggressive breast cancer subtypes and reduced survival. Coagulation may be a therapeutic target in breast cancer.


DCIS; PAR1; PAR2; breast cancer; coagulation; fibroblast; thrombin; thrombosis; tissue factor

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