Epithelial ovarian cancer usually presents with widespread disease throughout the peritoneal cavity and lymphatic channels, which leads to a dismal 15% 10-year survival. CSF-1, an essential cytokine in macrophage activation, confers invasive properties and a poor prognosis to ovarian cancers. Overexpression of CSF-1 and its receptor (encoded by the c-fms proto-oncogene) in ovarian cancer specimens are independently predictive of a poor outcome. CSF-1 is expressed at low levels in normal ovarian epithelium, but is overexpressed in many ovarian cancers. Moreover, ovarian cancer cells engineered to overexpress CSF-1 are significantly more invasive and metastatic. We show that an AU-rich 144nt region of exon 10 CSF-1 contains a strong negative regulatory element for CAT reporter expression, conferring CAT mRNA decay. We discovered a 22kDa cytoplasmic protein, whose synthesis appears to be stimulated by androgens, which binds to these CSF-1 sequences, and which is abundant in malignant cells, but barely detectable in normal ovarian cells. Deletion of the AU-rich region of exon 10 CSF-1 abolishes CSF-1 RNA protein binding. We hypothesize that in ovarian cancer cells, the exon 10 CSF-1 RNA binding protein, by binding to the AU-rich region of exon 10 CSF-1 RNA, stabilizes CSF-1, allowing for the aberrant expression of CSF-1 protein and the emergence of the invasive, metastatic phenotype. Further, that androgens, at least in part through the actions of CSF-1, impart a tumorigenic phenotype to normal ovarian epithelium.
We aim to (1) map the CSF-1 RNA protein binding site (2) clone the exon 10 CSF-1 RNA binding protein (3) determine if overexpression of this protein and/or androgens promote a tumorigenic phenotype to normal ovarian cells (4) study the effects of inhibition of CSF-1 RNA protein binding on CSF-1 expression and on inhibition of the invasive and metastatic behavior of ovarian cancer cells (5) determine the clinical significance of proteins related to androgen function in normal, benign, and malignant ovarian cancer specimens. These studies are necessary in order to design molecular therapies for patients that decrease CSF-1 levels in their tumors, and thereby contribute to suppression of invasive and metastatic ovarian cancer behavior. Moreover, the results of these studies will provide the scientific basis for a future trial of anti-androgen therapy as a chemopreventative agent in patients at high risk for the development of ovarian cancer.
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