Abstract 1062: Identification of flotilin-1 as an H-Ras-interacting lipid raft protein: Its implications in breast epithelial cell invasion

Abstract Metastatic spread is the major cause of death from breast cancer. We previously showed that H-Ras, but not N-Ras, induces invasive/migratory phenotypes of MCF10A human breast epithelial cells, while both H-Ras and N-Ras induce proliferation/transformation. Here, we identified flotillin-1 as an H-Ras-induced lipid raft protein through comparative proteome profiling of lipid raft proteins. Flotillin-1 interacts with H-Ras in lipid raft at a higher affinity than with N-Ras, elucidating a molecular nature of the crucial link between lipid rafts and the function of H-Ras. Small interfering RNA (siRNA)-mediated flotillin-1 knockdown significantly reduced H-Ras activation and H-Ras-mediated motility/invasion in MCF10A cells engineered to express H-Ras and in highly invasive human breast carcinoma Hs578T cells that express endogenous H-Ras. These results suggest a positive signal amplification loop between flotillin-1 and H-Ras for the invasive signaling program in breast epithelial cells. Importantly, tissue microarrays of 289 patients with invasive breast cancer revealed that flotillin-1 expression positively correlates with lymph node metastases (p=0.027), HER2/neu oncogene expression (p<0.001), and high histologic grade (p=0.014). Although infrequent, the membranous flotillin-1 expression is significantly associated with poor disease-free survival of patients (p=0.005), suggesting the clinical importance of predicting the characteristics of a small subpopulation of malignant breast cancer. Taken together, our findings provide new insight into the molecular basis of the Ras isoform-specific signaling mechanism that depends on the lipid-based sorting platforms. [This work was supported by the Korea government (Nos.ROA-2008-000-20070-0)] Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1062. doi:10.1158/1538-7445.AM2011-1062