Targeting Tissue Factor-Factor VIIa Signaling Pathway to Enhance Activity of mTOR Inhibitors in the Treatment of Breast Cancer

摘要

Tissue factor (TF) is a 47 kDa transmembrane glycoprotein that complexes with activated factor VII (FVIIa) to initiate blood coagulation. Breast cancer tumors and cell lines that have high expression of TF appear to be aggressive and have high metastatic potential. Formation of the TF-FVIIa complex induces signaling that leads to activation of p44/42 mitogen-activated protein kinase and protein kinase B (Akt) pathways and inhibition of apoptosis in breast cancer cells. The Akt-mammalian target of rapamycin (mTOR) pathway regulates cell growth and survival and plays a major role in the pathogenesis of breast cancer. Inhibition of mTOR has been shown to increase TF expression in some cell types which might increase tumor TF expression leading to enhanced TF-mediated signaling as well as an increased hypercoagulable state. Inhibition of mTOR, downstream of Akt, is a recent, emerging strategy in the treatment of breast cancer. In this proposal we test the hypothesis that the TF-VIIa signaling pathway interacts with the mTOR pathway to play a critical role in promoting dysregulated proliferation of breast cancer cells. In the present study, we show that formation of TF-FVIIa-FXa complex induces phosphorylation of mammalian target of rapamycin (mTOR) and p70 S6 kinase in a human breast cancer cell line, Adr-MCF-7. Activation of the mTOR pathway, which is probably mediated by PAR1 and/or PAR2, was associated with enhanced cell migration, a key step in the metastatic cascade. Inhibition of this pathway with the specific mTOR inhibitor, rapamycin, markedly decreased cell migration induced by formation of TF-FVIIa-FXa complex and modestly increased tumor cell TF expression. Targeting the TF-mediated cell signaling pathway along with mTOR inhibition might represent a novel strategy for the treatment of breast cancer.