Serine proteases and serine protease inhibitors in breast cancer cell pathophysiology Public Deposited

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Last Modified
  • March 21, 2019
Creator
  • Gramling, Mark W.
    • Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine
Abstract
  • Hemostasis and fibrinolysis are mediated by serine proteases and regulated by serine protease inhibitors, or serpins. There is a growing body of evidence that a few of these serine proteases and serpins have direct effects on cancer pathophysiology. Activated protein C (APC) is a serine protease that limits excessive clot formation by catalyzing inactivation of other coagulation factors. APC has also been shown to have non-hemostatic functions related to inflammation, angiogenesis, and cell migration. Therefore, we investigated the mechanisms by which APC could promote angiogenesis and breast cancer invasion. We confirmed that proteolytically active APC promotes angiogenesis by a mechanism dependent on matrix metalloprotease (MMP) activity and EGFR transactivation. Furthermore, we show that APC promotes breast cancer cell invasion by a similar mechanism and also show that APC induced cancer cell invasion is dependent upon activation of intracellular signaling pathways, specifically MAPK and PI3K signaling. Another serine protease, urokinase plasminogen activator (uPA), initiates fibrinolysis by activating plasmin - the protease which catalyzes degradation of fibrin clots. uPA activity is inhibited by the serpin plasminogen activator inhibitor 1 (PAI-1). Outside of fibrinolysis, uPA and PAI-1 are regulators of tumor cell motility through the focusing of their activities at the cancer cell surface. In breast cancer, clinical studies have demonstrated that elevation of both uPA and PAI-1 in tumor biopsies is predictive of poor prognosis. Therefore, we utilized breast cancer cell lines to investigate a possible direct mechanism whereby elevation of both uPA and PAI-1 could provide a survival advantage to breast cancer cells. Utilizing inhibitors of uPA and PAI-1 activity, as well as stable knockdown of each factor individually, we demonstrate that uPA promotes cell growth via activation of MAPK signaling. We also demonstrate that the catalytic function of both uPA and PAI-1 promote cell growth. We found PAI-1 is a key regulator of both MAPK signaling and anti-apoptotic PI3K signaling. Finally, we found that PAI-1 protects breast cancer cells from apoptosis inducing chemotherapeutic drugs, suggesting a direct mechanism whereby PAI-1 elevation is associated with poor prognosis in breast cancer.
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  • In Copyright
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  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Pathology and Laboratory Medicine."
Advisor
  • Church, Frank C.
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  • Chapel Hill, NC
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  • Open access
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