Abstract 4668: Pro-inflammatory lipid PAF may induce malignant potential via PAFR and phospho-FAK/STAT pathway in BRCA1-positive tubo-ovarian epithelial cells

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC The loss of BRCA1 function may induce profound transcriptional changes, phenotypic reprogramming and ultimately, generate genetically unstable tumor-initiating cells, which significantly increase the risk of breast and ovarian cancer. The molecular targets and pathways involved in early events of malignant transformation of at-risk epithelium has not been well investigated, particularly the effects of chronic inflammation. In an earlier study, we demonstrated that platelet activating factor (PAF), a potent pro-inflammatory mediator, plays a significant role in ovarian cancer progression and invasion (Cancer Research, 68:5839, 2008). Here, we extend our finding to show that PAF receptor is over expressed in BRCA1-mutated (BRCA1+) human ovarian surface epithelial cells (HOSE) by western blot and in distal fallopian tube (fimbria) epithelial cells by immunohistochemistry. In addition, PAF induced cell apoptosis only in wild type HOSE cells, and anti-apoptosis in BRCA1+ ovarian surface epithelial cells. A kinase microarray revealed that phosphor-STAT1/3/4/6 was simultaneously activated by 100 nM PAF treatment in BRCA1+ ovarian cancer cells. Induction of phosphor-STAT1 associated with PAFR and BRCA1-mutation was further confirmed in three BRCA1+ HOSE cell lines, but not in normal (HOSEE6E7) or malignant (OVCA429) ovarian epithelial cells. Co-immune precipitation revealed that PAF/PAFR coordinately activates FAK through dephosphorylation and STAT1 through phosphorylation only in BRCA1+ ovarian epithelial cells. These findings strongly suggest that potent inflammatory mediators (i.e. PAF) may play a significant role to induce malignant transformation in BRCA1-mutant ovarian epithelial cells through the FAK-STAT pathway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4668.