In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 4165-4165
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. 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 active H-Ras as well as in Hs578T breast carcinoma and T24 bladder carcinoma cells that express endogenous active mutant of H-Ras. These results suggest a positive signal amplification loop between flotillin-1 and H-Ras for the invasive signaling program. Flotillin-1 was crucial for the activation of the Ras-GRF1 exchange factor and its interaction with H-Ras in lipid rafts. Using a xenograft tumor model, we show that knockdown of flotillin-1 reduces the tumor growth in vivo. Importantly, tissue microarrays of 289 breast cancer patients revealed that flotillin-1 expression in the plasma membrane positively correlates with HER2/neu expression(p & lt;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 leading to cell invasion that depends on the lipid-based sorting platforms. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4165. doi:1538-7445.AM2012-4165
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2012-4165
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2012
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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