Tumors are replete with serine- and metallo-proteases produced by activated stromal cells, immune cells, and endothelial cells as well as by tumor cells themselves. Proteases alter cell-cell and cell-extracellular matrix interactions, and increase the activity of growth factors and growth factor receptors; these are critical processes for tumor cell growth, invasion and metastasis. Protease-activated receptors are G protein-coupled receptors (GPCRs) that are uniquely activated by proteolysis. Several tumor generated serine- and metallo-proteases are capable of cleaving and activating protease-activated receptor-1 (PAR1) and PAR2. Thus, PARs provide an important link between proteases generated in the tumor microenvironment and activation of GPCRs expressed on tumor cells. Aberrant PAR1 expression and signaling has been correlated with the invasive and metastatic properties of breast carcinomas. We recently determined that PAR2, a second protease-activated GPCR, is also important for breast cancer cell migration and invasion. Given the importance of proteases in cancer progression, we hypothesize that PAR signaling pathways are also critical, and are likely to be unique since all other GPCRs are reversibly activated. The long-term goal of these studies is to define the functional importance of PAR1 versus PAR2 in breast cancer cell invasion and metastasis. We propose the following specific aims: (1) to define the functional importance of PAR1 versus PAR2 in breast cancer cell invasion and metastasis in vitro and in vivo, and (2) to delineate the role of dysregulated PAR1 and PAR2 signaling in breast cancer cell growth, invasion and metastasis. Results from pursuit of these aims will illuminate uncharacterized vital roles of PARs in breast cancer cell growth, invasion and metastasis. This will have far-ranging implications including new insights into the molecular basis of breast cancer disease and new targets for anti-cancer drug discovery. ? ? ?
