{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:16:08Z","timestamp":1790745368323,"version":"4.1.0"},"reference-count":46,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2020,1,21]],"date-time":"2020-01-21T00:00:00Z","timestamp":1579564800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000691","name":"Academy of Medical Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2020,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Tumor stroma, of which fibroblasts are the most abundant cell, resembles a non\u2010healing 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\u2010free survival (DFS), and overall survival (OS).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In a prospective cohort of early breast cancer (DCIS, n\u00a0=\u00a076; invasive, n\u00a0=\u00a0248) tumor, normal breast and plasma were examined. Fibroblast and epithelial expression of Tissue Factor\u00a0(TF), thrombin, PAR1, PAR2, and plasma thrombin\u2010antithrombin (TAT) and D\u2010dimer were correlated with clinicopathological data, and 5\u2010year survival.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Fibroblast expression of TF, thrombin, and PAR1 was increased in DCIS and invasive cancer compared to normal breast fibroblasts (<jats:italic>P<\/jats:italic>\u00a0\u2264\u00a0.003, all). Fibroblast TF, thrombin, PAR1, and PAR2 was increased in cancers with high Ki67, high grade, ER\u2010\u00a0(vs ER+), and HER2+ (vs HER2\u2010) (all <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a0.05). On univariate analysis, fibroblast TF expression was inversely associated with DFS (<jats:italic>P<\/jats:italic>\u00a0=\u00a0.04) and OS (<jats:italic>P<\/jats:italic>\u00a0=\u00a0.02). D\u2010dimer was higher in node positive (507 (CI: 411\u2010625)\u00a0ng\/mL, n\u00a0=\u00a068) vs negative patients\u00a0(428 (CI: 387\u2010472)\u00a0ng\/mL, n\u00a0=\u00a0171, <jats:italic>P<\/jats:italic>\u00a0=\u00a0.004) and inversely associated with OS (<jats:italic>P<\/jats:italic>\u00a0=\u00a0.047). On multivariate analysis, plasma TAT was associated with reduced OS (HR 3.26, CI 1.16\u20103.1, <jats:italic>P<\/jats:italic>\u00a0=\u00a0.02), with a high plasma TAT (\u22653.2\u00a0ng\/mL) associated with\u00a0&gt;\u00a03\u2010fold mortality risk compared to low TAT.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cam4.2748","type":"journal-article","created":{"date-parts":[[2020,1,21]],"date-time":"2020-01-21T20:22:37Z","timestamp":1579638157000},"page":"1768-1778","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Breast cancer stromal clotting activation (Tissue Factor and thrombin): A pre\u2010invasive phenomena that is prognostic in invasion"],"prefix":"10.1002","volume":"9","author":[{"given":"Hudhaifah","family":"Shaker","sequence":"first","affiliation":[{"name":"Faculty of Biology, Medicine and Health Division of Cancer Sciences School of Medical Sciences Manchester Cancer Research Centre University of Manchester Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6007-056X","authenticated-orcid":false,"given":"Nigel J.","family":"Bundred","sequence":"additional","affiliation":[{"name":"Faculty of Biology, Medicine and Health Division of Cancer Sciences School of Medical Sciences Manchester Cancer Research Centre University of Manchester Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00f6ran","family":"Landberg","sequence":"additional","affiliation":[{"name":"Department of Pathology Institute for Biomedicine Sahlgrenska Cancer Center University of Gothenburg Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan A.","family":"Pritchard","sequence":"additional","affiliation":[{"name":"Department of Histopathology Manchester University NHS Foundation Trust Wythenshawe, Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harith","family":"Albadry","sequence":"additional","affiliation":[{"name":"Department of Histopathology Royal Liverpool and Broadgreen University Hospitals NHS Trust Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah L.","family":"Nicholson","sequence":"additional","affiliation":[{"name":"Department of Histopathology East Lancashire Hospitals NHS Trust Blackburn UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren J.","family":"Harries","sequence":"additional","affiliation":[{"name":"Department of Histopathology Manchester University NHS Foundation Trust Wythenshawe, Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing Y. 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