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Control of Transformation and Invasiveness of Breast Cancer Cells by Estrogen Regulation of Proteinase Inhibitor 9

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Annual summary rept. 1 Apr 2003-31 Mar 2004

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Coagulation factor VIIa, a circulating serine protease, binds to its cofactor, tissue factor TF, to trigger the blood clotting cascade. TF is a glycoprotein present on the surface of a variety of cell types found outside of the vasculature, and various types of cancer cells. TFVIIa complex formation ultimately leads to fibrin polymerization and platelet activation, in both hemostasis and thrombotic disease. Complex formation has also been shown to activate certain signaling cascades, altering cellular properties such as adhesion, migration, and apoptotic potential. Many types of cancer cells have been shown to express high levels of TF. Blockage with anti-TF antibodies has demonstrated that metastasis depends on the presence of catalytically competent TFVIIa complexes. Such cellular alterations, high morbidity associated with thrombosis, and the privileged position of VIIa in the coagulation cascade, make inhibition of TFVIIa an important issue in cancer therapy. We have demonstrated that antithrombin AT can inhibit TFVIIa, when in the presence of heparin, and ATVIIa complexes have been detected in plasma, suggesting that Vita is inhibited by AT in vivo. We have also shown that AT can reversibly inhibit factor VIIa in vitro and in plasma, and are currently beginning studies in breast cancer and endothelial cells.

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  • Anatomy and Physiology
  • Medicine and Medical Research

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