Abstract P4-02-08: STAT Signaling in Endocrine Sensitive and Resistant Breast Cancer — A Potential Target for Therapy?

Abstract

Abstract The STAT (for signal transducer and activators of transcription) family of molecules regulate cell growth, survival, and differentiation as important integrators of cytokine and growth factor receptor signaling. STAT3 and STAT5 have been implicated in endocrine resistance in breast cancer. We aimed to identify new modifiers of endocrine sensitivity in breast cancer using functional proteomic profiling of the estrogen/tamoxifen-sensitive MCF-7 cell line and its partially sensitive (LCC1) and fully resistant (LCC9) variants. Using an unsupervised analysis of the expression of 125 paired phosphorylated and non-phosphorylated epitopes in key oncogene and tumour suppressor pathways on antibody arrays, STAT1, STAT3, and their phosphorylated epitopes were differentially expressed between endocrine resistant and parental controls. Differential expression was confirmed by qRT-PCR and western blotting. The STAT1 inhibitor EGCG inhibited cell number in endocrine insensitive and resistant LCC1/LCC9 lines, while the STAT3 inhibitors static and WP1066 were equally effective in endocrine-resistant and parental lines. Reduction in cell number was shown to be due to induction of apoptosis rather than inhibition of proliferation. The effects of the STAT inhibitors were additive, rather than synergistic, when tested in combination with tamoxifen in vitro. Finally, expression of STAT 1 and STAT3 were measured by quantitative immunofluorescence in 54 invasive breast cancers and expression levels of STAT1 and STAT3 transcript analysed in 550 breast cancers from publicly available gene expression datasets (GSE2990, GSE12093, GSE6532). High expression of STAT1, and low expression of STAT3, were associated with a worse distant metastasis free survival (DMFS; RR 1.42 and 0.46; log-rank p=0.042 and P<0.0001, respectively). When treatment with tamoxifen was considered, STAT1 expression was nearly predictive of DMFS (log-rank p=0.067), while STAT3 expression was predictive of DMFS (log-rank P<0.0001). These results suggest that STAT signaling may be important in endocrine resistance, and that STAT inhibitors, particularly STAT1 inhibitors, may be effective therapies in breast cancer even in the resistant setting. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-02-08.