This Section has focused on the role of Ca++ as a regulator of gene expression and cellularPhysiology and application of novel technologies to functional gene discovery in epithelial ovarian cancer. We have investigated Ca++-regulated molecular events. We continue to study the signal transduction function of CAIR-1/BAG-3. We have demonstrated by cellular fractionation and immunohistochemistry that CAIR-1 is a cytosolic signaling protein. Clinical correlative studies are ongoing to assess the role of CAIR-1 expression in epithelial cancers. CAIR-1 function studies are being driven by functional domains and their cognate parters. Our hypothesis that CAIR-1 should function downstream of a calcium-regulated or calcium-associated pathways led to the identification of phospholipase C-gamma (PLC-g) as a putative partner protein. Coimmunoprecipitation studies indicate that CAIR-1 binds to PLC-g under basal conditions and is dissociated when cells are stimulated with epidermal growth factor. This binding requires the CAIR-1 PXXP binding to the SH3 domain of PLC-g. Binding to HSP- and HSC-70 occurs through the BAG domain, C-terminal to the PXXP region and is not EGF sensitive. Gene discovery was accomplished using cDNA libraries generated from microdissected ovarian cancer epithelium. A relatively new growth factor was shown to be differentially expressed between invasive ovarian cancer and tumor of low malignant potential. This finding was validated in a cohort of patient samples by RT-PCR and immunohistochemistry. IHC showed stroma of both tumor types also expressed this growth factor suggesting that there may be a microenvironment event as well. Further studies are ongoing to characterize this growth factor in ovarian cancers.
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