B Kocatürk1, C Tieken1, D Vreeken1, B Ünlü1, C C Engels2, E M de Kruijf2, P J Kuppen2, P H Reitsma1, V Y Bogdanov3, H H Versteeg1. 1. Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands. 2. Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands. 3. Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Abstract
BACKGROUND: Procoagulant 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. OBJECTIVE: To investigate whether TF isoform-specific and ER-dependent pathways interact in BrCa. METHODS: Tissue 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 in vivo growth in the presence or absence of estradiol. RESULTS: Ingenuity 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 β1 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 in vivo in an orthotopic setting. CONCLUSION: Tissue 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.
BACKGROUND: Procoagulant 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. OBJECTIVE: To investigate whether TF isoform-specific and ER-dependent pathways interact in BrCa. METHODS:Tissue factor isoform-regulated gene sets were assessed using ingenuity pathway analysis. Tissues from a cohort of BrCapatients 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 in vivo growth in the presence or absence of estradiol. RESULTS: Ingenuity 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 β1 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 in vivo in an orthotopic setting. CONCLUSION:Tissue 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.
Authors: Osvaldo Pontiggia; Rocio Sampayo; Diego Raffo; Andrea Motter; Ren Xu; Mina J Bissell; Elisa Bal de Kier Joffé; Marina Simian Journal: Breast Cancer Res Treat Date: 2011-09-21 Impact factor: 4.872
Authors: Johanna G H van Nes; Esther M de Kruijf; Dana Faratian; Cornelis J H van de Velde; Hein Putter; Claire Falconer; Vincent T H B M Smit; Charlene Kay; Marc J van de Vijver; Peter J K Kuppen; John M S Bartlett Journal: Breast Cancer Res Treat Date: 2010-04-01 Impact factor: 4.872
Authors: Y W van den Berg; L G van den Hengel; H R Myers; O Ayachi; E Jordanova; W Ruf; C A Spek; P H Reitsma; V Y Bogdanov; H H Versteeg Journal: Proc Natl Acad Sci U S A Date: 2009-10-29 Impact factor: 11.205
Authors: Vladimir Y Bogdanov; Viji Balasubramanian; James Hathcock; Oana Vele; Mark Lieb; Yale Nemerson Journal: Nat Med Date: 2003-03-24 Impact factor: 53.440