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Review
. 2014 Dec 10;5(5):908-20.
doi: 10.5306/wjco.v5.i5.908.

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

Shiro Koizume  1 , Yohei Miyagi  1
Affiliations
Review

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

Shiro Koizume et al. World J Clin Oncol. .

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.

Keywords: Blood coagulation; Breast cancer; Coagulation factor VII; Gene regulation; Therapeutic strategy; Tissue factor.

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Figures

Figure 1
Figure 1
Extrinsic coagulation cascade initiated by the tissue factor-coagulation factor VII pathway. TF-fVIIa complex formation on the plasma membrane triggers an extrinsic coagulation cascade in response to injury. The TF-fVIIa complex located on the cell surface initiates the coagulation cascade by activating factor X via two different (coagulation factor IX-dependent or -independent) routes. This leads to fibrin deposition via the formation of thrombin. Blood coagulation completes by clot formation with other factors, such as platelets and red blood cells. FVII: Coagulation factor VII (fVII); TF: Tissue factor.
Figure 2
Figure 2
Activation of protease-activated receptors is a major mechanism of tissue factor-coagulation factor VIIa signaling in breast cancer cells. The proteolytic activities of the TF-fVIIa binary complex [potentially (designated as dotted line) ternary complex with fXa] cleave the N-terminal end of PARs. PARs are then activated via intra-molecular binding between the newly created N-terminus and an extracellular loop region of the receptors. Activation of these G-protein-coupled receptors subsequently activates downstream signaling cascades. A number of studies have indicated that PAR2 is crucial for activation of a TF-fVII-driven signaling cascade in breast cancer cells. The role of TF-fVII on PAR1 signaling in breast cancer cells is less evident. FVII: Coagulation factor VII; TF: Tissue factor; PARs: Protease-activated receptors.
Figure 3
Figure 3
Possible mechanisms of expression and functional regulation of tissue factor and coagulation factor VII in breast cancer cells. Schematic overview summarizing the multiple mechanisms of gene expression, functional tuning, and intracellular signaling in breast cancer cells, as described in this review. It has been suggested that breast cancer cell phenotypes associated with the TF-fVII pathway may be specifically controlled via multiple autocrine and/or paracrine mechanisms, depending on tumor microenvironmental conditions. EGFR: Epidermal growth factor receptor; EPCR: Endothelial protein C receptor; FVII: Coagulation factor VII; TF: Tissue factor.
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