Ovarian cancer is the fifth most common cause of death from cancer in women. The 5-year survival rates for late stage ovarian cancer is 20-25%. Secretory leukocyte proteinase inhibitor (SLPI) is a serine proteinase inhibitor, for which mRNA and protein are upregulated in epithelial ovarian cancers compared to normal ovarian epithelium. Moreover, SLPI overexpression in ovarian cancer is associated with more progressive and high-risk ovarian tumors, contributing to a poorer prognosis. Previously, we have shown that SLPI functions as a growth factor by promoting cellular proliferation in ovarian cancer. We hypothesized that overexpression of the SLPI protein promotes invasion and metastasis in ovarian cancer cells. In order to gain further insight on SLPI and its likely role in more aggressive tumors, we overexpressed two proteinase inhibitor site mutants, F-SLPI (72 Phe) and R-SLPI (72Arg), with known decreased protease inhibitory capability. Xenographs of Hey A8 ovarian cancer cell line overexpressing SLPI and SLPI-mutants revealed greater tumor size and areas of invasion and metastasis in nude mice, when compared to mock-transfected cells. Zymogram analysis of conditioned medium from serum-starved SLPI and SLPI-mutant transfected HEY A8 cells had increased gelatinolytic activity corresponding to both matrix metalloproteinase (MMP) -2 and -9. Immunoassay evaluating MMP-9 quantity demonstrated a statistically significant increase of MMP-9 at 48-hour serum starvation incubation, in SLPI-mutant transfected cells lines compared with mock- and SLPI-transfected cells (p<0.001 and p<0.0001, respectively). Although not statistically significant, increased secretion of MMP-2 was observed in the conditioned medium of SLPI-mutant cells. We are currently investigating mechanisms by which SLPI and SLPI-mutated cells contribute to more aggressive tumors. Disruption of SLPI with a novel molecular target may aide in treatment of ovarian cancer.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA