Journal
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
Volume 13, Issue 9, Pages 1683-1693Publisher
WILEY
DOI: 10.1111/jth.13049
Keywords
blood coagulation; cell movement; cell proliferation; integrin beta1; tumors
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Funding
- NCI NIH HHS [1R21CA160293, R21 CA160293] Funding Source: Medline
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BackgroundProcoagulant full-length tissue factor (flTF) and its minimally coagulant alternatively spliced isoform (asTF), promote breast cancer (BrCa) progression via different mechanisms. We previously showed that flTF and asTF are expressed by BrCa cells, resulting in autoregulation in a cancer milieu. BrCa cells often express hormone receptors such as the estrogen receptor (ER), leading to the formation of hormone-regulated cell populations. ObjectiveTo investigate whether TF isoform-specific and ER-dependent pathways interact in BrCa. MethodsTissue factor isoform-regulated gene sets were assessed using ingenuity pathway analysis. Tissues from a cohort of BrCa patients were divided into ER-positive and ER-negative groups. Associations between TF isoform levels and tumor characteristics were analyzed in these groups. BrCa cells expressing TF isoforms were assessed for proliferation, migration and invivo growth in the presence or absence of estradiol. ResultsIngenuity pathway analysis pointed to similarities between ER- and TF-induced gene expression profiles. In BrCa tissue specimens, asTF expression was associated with grade and stage in ER-positive but not in ER-negative tumors. flTF was only associated with grade in ER-positive tumors. In MCF-7 cells, asTF accelerated proliferation in the presence of estradiol in a 1 integrin-dependent manner. No synergy between asTF and the ER pathway was observed in a migration assay. Estradiol accelerated the growth of asTF-expressing tumors but not control tumors invivo in an orthotopic setting. ConclusionTissue factor isoform and estrogen signaling share downstream targets in BrCa; the concomitant presence of asTF and estrogen signaling is required to promote BrCa cell proliferation.
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