Brandi Whiltley Hilder, Ph.D.

Dissertation research performed under the direction of Frank C. Church

ABSTRACT
    The development of cancer is a multi-step progression of a clonal population of cells that acquires the ability to proliferate uncontrolled, to migrate from the primary tumor site, to invade at distant sites, and finally to establish metastases. This process can be facilitated by serine proteases and regulated by serine protease inhibitors (serpins). Plasminogen activator inhibitor-1 (PAI-1) is a serpin that regulates the urokinase-type plasminogen activator (uPA), thus modulating extracellular matrix (ECM) degradation in cancer biology. Increased expression of PAM is associated with poor prognosis and decreased overall survival in breast and ovarian cancers. This in vivo evidence seemingly contradicts the proposed role for PAI-1 to protect the ECM from uPA-mediated degradation. Consequently, alternate roles for PAI-1 have been established, including regulating cell adhesion, cell migration, cell invasion, angiogenesis, wound healing, cell proliferation and survival, and cell signaling. Thus, we investigated the interactions required for PAI-1 regulation of cell migration and invasion in breast and ovarian cancer cell lines using different PAI-1 mutants, expressed by stable transfection, adenoviral-mediated delivery, or added exogenously as recombinant PAI-1 proteins. We also explored the regulation of PAI-1 expression by various signaling pathways and attempted to relate this regulation to cell migration and cell invasion capabilities.