Area of interest
One in nine women will be diagnosed with breast cancer. A significant percentage of women will already have metastatic cancers at the time of diagnosis and even though the 5-year survival rates have improved, a majority of women will still succumb to recurrent disease. To develop metastatic disease, the extracellular matrix surrounding the cancer must be degraded, allowing cancer cells to travel to distant sites. Matrix degradation is mediated by proteases, one of which is urokinase plasminogen activator (uPA). A specific inhibitor, plasminogen activator inhibitor-1 (PAI-1), regulates uPA activity. Surprisingly, an elevated level of PAI-1 is a poor prognostic factor for breast cancer patients. It is unclear why a substance that blocks matrix degradation would be linked to a poor prognosis. Our objective is to understand the “paradox” of why too much PAI-1 is detrimental to women with breast cancer. We believe that expression of PAI-1 confers a survival advantage upon breast cancer cells. Our results will shed valuable information on the role of PAI-1 in one of the most significant problems hindering the treatment of women with breast cancer, invasion and metastasis.
Understanding recurrent disease is one of the most critical areas of ovarian cancer biology and fundamental for the development of effective treatment regimens. The vast majority of women diagnosed with ovarian cancer will experience recurrent disease within 5 years. Treatment options for these patients are often limited. The seeding of metastatic tumor masses throughout the peritoneal cavity marks recurrent ovarian cancer. Metastatic cancers are the result of the migration of cells from the initial tumor mass and occur following both loss of adhesion between cells and the extracellular matrix and significant alterations in the cell architecture. The destruction of adhesive contacts is made in part by members of the plasminogen activator family. Expression of urokinase plasminogen activator (uPA) and its inhibitor (PAI-1) have been shown to be up-regulated in the majority (>50%) of ovarian cancers and are independent poor prognostic factors for patient survival. As with other cancers, uPA expression and activity is believed to be critical for metastasis. We are studying ovarian tumor cells lines and their ability to adhere, migrate and invade in an in vitro environment, and the signaling process that is transmitted by the plasminogen activator system. We are studying by immunohistochemistry, the occurrence of serpins and their proteases in primary and metastatic ovarian cancer. We believe that the results of this work will ultimately benefit women with metastatic, recurrent ovarian cancer.