Ectopic Synthesis of Coagulation Factor VII in Breast Cancer Cells: Mechanisms, Functional Correlates, and Potential for a New Therapeutic Target

Abstract

Recent advances in the development of therapeutic strategies have enabled the cure of a considerable amount of cases of breast cancer patients. However, breast cancer is a worldwide problem since this disease remains a common cause of cancer death in women throughout the world (Alvarez 2010). Although breast cancer can be regulated by chemotherapy, there are still difficulties with treating recurrence and triple-negative breast cancer without therapeutic molecular targets (HER2 and hormone receptors) (Foulkes et al. 2010). Therefore, it is necessary to increase the knowledge of breast cancer biology and investigate target molecules to facilitate therapeutic strategy toward aggressive breast cancers. Hypercoagulation is a common complication of cancer patients and also correlates with mortality (Ten Cate & Falanga 2007). In fact, it has been reported that the risk of venous thromboembolism (VTE) is highest for cancers of the ovary, pancreas, liver (Iodice et al., 2008), and breast during chemotherapy (Kirwan et al. 2008). Blood coagulation factor VII (fVII) is a key enzyme of the extrinsic coagulation cascade that is produced predominantly by hepatocytes (Furie & Furie 1988). Tissue factor (TF) is a 47kD transmembrane glycoprotein and a cellular receptor of fVII. Blood coagulation factor VII from blood plasma bound to TF is converted to its active form (fVIIa) and activates a downstream extrinsic coagulation cascade, leading to fibrin deposition (Fig. 1). It has been reported that plasma TF levels are higher in cancer patients including advanced breast cancer (Ueno et al. 2000). Furthermore, breast cancer cells secrete cell membranederived microvesicles containing TF antigen under pathological conditions, resulting in coagulation activation (Davila et al. 2008). Therefore, TF-fVIIa formation can be a major cause of thromboembolic disease. A number of studies have demonstrated that tissue factor-fVIIa complex formation on the cell surface also initiates key pathogenic events including activation of cell motility, invasiveness, cell survival, and angiogenesis (Milsom & Rak 2009). Recently, growing experimental evidence has also suggested that TF contributes to tumor initiation (Milsom & Rak 2009). Given that fVII presents on the invasive edge of various cancer tissues (Fischer et al. 1999;