Breast cancer phenotypes regulated by tissue factor-factor VII pathway: Possible therapeutic targets

Abstract

Breast cancer is a leading cause of cancer death in women, worldwide. Fortunately, breast cancer is relatively chemosensitive, with recent advances leading to the development of effective therapeutic strategies, significantly increasing disease cure rate. However, disease recurrence and treatment of cases lacking therapeutic molecular targets, such as epidermal growth factor receptor 2 and hormone receptors, referred to as triple-negative breast cancers, still pose major hurdles in the treatment of breast cancer. Thus, novel therapeutic approaches to treat aggressive breast cancers are essential. Blood coagulation factor VII (fVII) is produced in the liver and secreted into the blood stream. Tissue factor (TF), the cellular receptor for fVII, is an integral membrane protein that plays key roles in the extrinsic coagulation cascade. TF is overexpressed in breast cancer tissues. The TF-fVII complex may be formed in the absence of injury, because fVII potentially exists in the tissue fluid within cancer tissues. The active form of this complex (TF-fVIIa) may stimulate the expression of numerous malignant phenotypes in breast cancer cells. Thus, the TF-fVII pathway is a potentially attractive target for breast cancer treatment. To date, a number of studies investigating the mechanisms by which TF-fVII signaling contributes to breast cancer progression, have been conducted. In this review, we summarize the mechanisms controlling TF and fVII synthesis and regulation in breast cancer cells. Our current understanding of the TF-fVII pathway as a mediator of breast cancer progression will be also described. Finally, we will discuss how this knowledge can be applied to the design of future therapeutic strategies. Key words: Breast cancer; Blood coagulation; Tissue factor; Coagulation factor VII; Gene regulation; Therapeutic strategy Core tip: Breast cancer is a worldwide problem. Difficulties with treating the disease and its recurrence persist due, in part, to a lack of therapeutic molecular targets. Blood coagulation factor VII (fVII) is generally produced in the liver. Tissue factor (TF), the cellular receptor for fVII, is an integral membrane protein that plays key roles in the extrinsic coagulation cascade. Formation of the TF-fVII complex causes contributes to the malignant phenotype of breast cancer cells. In this review, we summarize the breast cancer biology associated with the TF-fVII pathway. Further, we will discuss how these mechanisms can be targeted as therapeutics for this aggressive disease.Koizume S, Miyagi Y. Breast cancer phenotypes regulated by tissue factor-factor VII pathway: Possible therapeutic targets.

Tissue Factor–Factor VII Complex as a Key Regulator of Ovarian Cancer Phenotypes

“…Tissue factor (TF) is an ~50-kDa transmembrane lipoprotein that functions as the cellular receptor for fVII. 5 , 6 The concentration of fVII in the human blood is the second lowest among plasma coagulation factors; 5 however, upon injury, fVII interacts with TF and accumulates on the exposed cell surface, leading to its conversion to the active form factor VIIa (fVIIa). 5 , 6 The serine protease activity of the TF–fVIIa complex initiates the blood coagulation cascade, thereby leading to fibrin deposition 5 , 6 ( Fig.…”

“…This binary complex also contributes to cellular angiogenic and inflammatory responses via phosphorylation of the cytoplasmic domain of TF, followed by activation of cellular signaling cascades. 6 , 7 …”

Factor VII Gene Defects: Review of Functional Studies and Their Clinical Implications

“…The catalytic regions exhibit the serine protease activity, which leads to various functions of the protein [18] . The role of FVII in the pathogenesis of various cancers has extensively been studied [19][20][21][22][23][24] . Though the molecular pathogenesis of the increased expression of FVII by cancer cells has not precisely been described, the ectopic expression of FVII may promote the division, migration, and invasion of cancer cells.…”

Granulocyte-Colony Stimulating Factor Receptor, Tissue Factor, and VEGF-R Bound VEGF in Human Breast Cancer In Loco

“…Coagulation factors and their receptors are not only essential players in the coagulation process, but they play an important role in the tumor biology [12]. Tissue factor (TF) is the main procoagulant, both under physiological conditions and in the state of neoplastic disease [13,14]. Additionally, it was documented that TF activity contributes to cancer progression and stimulation of new vessel formation at the tumor-host interface [14].…”

“…Tissue factor (TF) is the main procoagulant, both under physiological conditions and in the state of neoplastic disease [13,14]. Additionally, it was documented that TF activity contributes to cancer progression and stimulation of new vessel formation at the tumor-host interface [14]. Angiogenesis is an important process during cancer growth and metastatic dissemination [10,15,16].…”