The Role of Tissue Factor-Factor VIIa-PAR2 Signaling in Breast Tumor Progression

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

DESCRIPTION (provided by applicant): One of the most complex and elusive events in tumor biology is metastasis. This process by which tumor cells become metastatic has been a very active area of research with extremely important clinical implications. Tissue factor (TF) is a cell surface receptor that initiates the coagulation protease cascade. Factor Vila (FVIIa) docks to TF and the TF-FVIIa complex cleaves and activates protease activated receptor-2 (PAR2) thereby inducing downstream signaling. TF-FVIIa-PAR2 signaling increases a variety of genes including those involved in metastasis. Many studies have been performed on TF-FVIIa-PAR2 signaling in a human breast tumor model. However, the detailed mechanisms concerning how TF-FVIIa- PAR2 increases tumor cell metastasis have not been revealed. The 67NR and 4T1 cell lines were derived from a single spontaneously arising mouse breast tumor. The advantage of using this breast tumor model to study TF-FVIIa-PAR2 signaling is that these cells allow for in vivo studies in a non-genetically modified immunocompetent host. We hypothesize that the increased metastatic behavior exhibited by, aggressive, as opposed to non-aggressive cancer cells is due to differential TF-FVIIa-PAR2 signaling. The specific aims of the project are: 1) analyze TF-FVIIa-PAR2 signaling in metastatic and non-metastatic breast tumor cell lines in vitro;and 2) examine the contribution of TF-FVIIa-PAR2 signaling to cell motility in a metastatic and non- metastatic breast tumor model in vivo. The overall goal of this project is to detail the precise intracellular signal transduction pathways responsible for TF-FVIIa-PAR2 induced metastasis using an in vitro and in vivo model of murine breast cancer. Cancer is a pressing public health concern. By establishing a causative role of PAR2 in metastasis I hope to provide further insight into this complex pathophysiological process. Increased understanding of the metastatic disease process will enable the scientific and medical communities to make advances in therapeutics and treatment strategies.