A novel role for flotillin-1 in H-Ras-regulated breast cancer aggressiveness
- Int J Cancer. 2016 Mar 1;138(5):1232-45. doi: 10.1002/ijc.29869.
- 1. College of Pharmacy, Duksung Women's University, Seoul, Korea.
- 2. Department of Immunology, School of Medicine, Konkuk University, Chungju, Korea.
- 3. Department of Surgery and Cancer Research Institute, College of Medicine, Seoul National University, Seoul, Korea.
- 4. Department of Molecular Medicine, College of Medicine, Inha University, Incheon, Korea.
- 5. Department of Oral Physiology, School of Dentistry, Pusan National University, Yangsan, Korea.
- 6. Department of Cell and Developmental Biology, BK21 Program and Dental Research Institute, Seoul National University, Seoul, Korea.
- 7. Department of Pathology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
- 8. Department of Radiology, Seoul National University Hospital, Seoul, Korea.
- 9. Department of Pathology, Wayne State University School of Medicine, Detroit, MI.
Elevated expression and aberrant activation of Ras have been implicated in Breast Cancer aggressiveness. H-Ras, but not N-Ras, induces breast cell invasion. A crucial link between lipid rafts and H-Ras function has been suggested. This study sought to identify the lipid raft protein(s) responsible for H-Ras-induced tumorigenicity and invasiveness of Breast Cancer. We conducted a comparative proteomic analysis of lipid raft proteins from invasive MCF10A human breast epithelial cells engineered to express active H-Ras and non-invasive cells expressing active N-Ras. Here, we identified a lipid raft protein flotillin-1 as an important regulator of H-Ras activation and breast cell invasion. Flotillin-1 was required for epidermal growth factor-induced activation of H-Ras, but not that of N-Ras, in MDA-MB-231 Triple-Negative Breast Cancer (TNBC) cells. Flotillin-1 knockdown inhibited the invasiveness of MDA-MB-231 and Hs578T TNBC cells in vitro and in vivo. In xenograft mouse tumor models of these TNBC cell lines, we showed that flotillin-1 played a critical role in tumor growth. Using human Breast Cancer samples, we provided clinical evidence for the metastatic potential of flotillin-1. Membrane staining of flotillin-1 was positively correlated with metastatic spread (p = 0.013) and inversely correlated with patient disease-free survival rates (p = 0.005). Expression of flotillin-1 was associated with H-Ras in Breast Cancer, especially in TNBC (p < 0.001). Our findings provide insight into the molecular basis of Ras isoform-specific interplay with flotillin-1, leading to tumorigenicity and aggressiveness of Breast Cancer.