Abstract 3132: Proliferative effects of FGF1 on ovarian cancer cells correlate with FGFR4 over expression and are mediated by MAPK/ERK signaling

Abstract

Abstract Objectives: To identify the effect of FGF1 on cell proliferation in ovarian cancer and endothelial cells, its relation to FGFR4 over expression and signaling pathways involved Methods: Amplification of FGFR4 on 5q31-35, which was previously shown to be associated with poor survival in patients with advanced stage high-grade serous ovarian cancer (HGSC), was validated by quantitative PCR in 52 HGSC. Association between DNA copy numbers of FGFR4 and FGF1 located on the same segment was performed by Spearman correlation analysis. Over expression of FGFR4 protein was confirmed in ovarian cancer cell lines and tissue by western blot analysis and immunohistochemistry, respectively. Endogenous FGF1 production by several ovarian cancer cell lines in conditioned medium was quantified using ELISA. Effect of exogenous FGF1 on cell proliferation of high and low-FGFR4 expressing ovarian cancer cell lines and an immortalized microvascular endothelial cell line was determined by WST-1 assay. Signaling pathways activation was screened by treating ovarian cancer cell lines and endothelial cells transduced with six different transcription response elements using the Cignal-Lenti reporter system with exogenous FGF1. Results: FGFR4 was amplified and over-expressed in a majority of ovarian cancer cell lines and tumor tissue and FGFR4 DNA copy number was significantly correlated with that of FGF1 (r=0.4, p=0.04). Endogenous FGF1 production was detected by ELISA in 2 of 5 screened ovarian cell lines. FGF1 significantly induced cell proliferation in high FGFR4 expressing ovarian cancer cells (20%, p<0.001) and in endothelial cells (15%, p<0.001); but not in low FGFR4 expressers. Significant activation of MAPK/ERK signal transduction pathways was noted after treatment of ovarian(1.43 fold, P < 0.001) and endothelial(1.33 fold, P < 0.001) cell lines transduced with the Cignal-Lenti reporter system. Conclusions: Our report provides preliminary evidence that poor survival associated with FGF1 amplification and over expression appears to be mediated through FGFR4, which is also amplified and over-expressed in ovarian cancer cell. In addition, FGF1 produced by ovarian cancer cells may exert both autocrine and paracrine effect on cancer cells and endothelial cells through the activation of MAPK/ERK pathway. These data suggests that new regimens targeting FGF1, FGFR4 and downstream signaling pathways may improve ovarian cancer patient survival. 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 3132.