P5-06-06: The RNA Binding Protein FUS Is a Potential Marker for Breast Cancer Progression and Therapy Response.

Abstract Background The RNA binding protein FUS is a multifunctional protein that has recently been demonstrated to be directed to target genes via non-coding RNA, where it represses transcription via disruption of the transcriptional complex. We have shown that FUS is an important regulator of prostate cancer cell growth; FUS over-expression causes G1 arrest, promotes apoptosis and blocks proliferation in vitro and in vivo, whereas knock-down increases proliferation. This regulation appears to be, at least in part, via direct regulation of cyclin D1. Further, analysis of patient samples demonstrated that FUS levels are inversely correlated with Gleason grade and directly correlated with survival and the presence of bone metastases. We hypothesised that FUS is a predictive and/or prognostic marker for hormone-dependent cancers. Materials and Methods: FUS expression in breast cancer was analysed in silico and using Western blotting and immunohistochemistry on a tumour microarray. FUS levels were knocked down by siRNA in MCF-7 cells and chemosensitivity analysed using caspase 3/7 assays. Results: Analysis of the Finak dataset (2008) demonstrated that FUS expression is significantly lower in breast cancer compared to normal breast. Immunohistochemistry revealed that FUS expression is also inversely correlated with grade. Importantly, FUS expression was also correlated with survival (Kaplan-Meier Plotter); significantly longer relapse free survival was seen in patients whose tumours had high levels of FUS. FUS expression also appears to correlate with therapy response since analysis of the Chang dataset (2003) revealed that FUS levels are significantly lower in patients resistant to Docetaxel and we found FUS levels to be lower in the tamoxifen resistant MCF-7 cell line (MCF-7 TAMR) compared to the parental line. We therefore hypothesised that loss of FUS expression may be driving therapy failure. In support of this, reducing FUS expression in the parental MCF7 line resulted in a significant reduction in docetaxel-induced Caspase 3/7 activity, suggesting that FUS is a regulator of chemosensitivity. Discussion: FUS may be an important regulator of breast cancer progression since its levels are inversely correlated with grade and directly correlated with relapse free survival. Further, lower FUS expression is also correlated with reduced hormone therapy and chemo-sensitivity. Since knock-down of FUS reduced MCF-7 chemosensitivity, we believe that the observed changes in FUS expression are, in part, driving therapy failure and hence propose that FUS is a novel target and biomarker for breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-06-06.