A novel role for flotillin-1 in H-Ras-regulated breast cancer aggressiveness.

Abstract

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.

• Authors: Minsoo Koh, Hae-Young Yong, Eun-Sook Kim, Hwajin Son, You Rim Jeon, Jin-Sun Hwang, Myeong-Ok Kim, Yujin Cha, Wahn Soo Choi, Dong-Young Noh, Kyung-Min Lee, Ki-Bum Kim, Jae-Seon Lee, Hyung Joon Kim, Haemin Kim, Hong-Hee Kim, Eun Joo Kim, So Yeon Park, Hoe Suk Kim, Woo Kyung Moon, Hyeong-Reh Choi Kim, Aree Moon
• Journal: International journal of cancer (Int J Cancer) Vol. 138 Issue 5 Pg. 1232-45 (Mar 01 2016) ISSN: 1097-0215 [Electronic] United States
• PMID: 26413934 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 UICC.

Chemical References

• Membrane Proteins
• flotillins
• Phosphatidylinositol 3-Kinases
• EGFR protein, human
• ErbB Receptors
• Proto-Oncogene Proteins c-akt

Topics

• Adult
• Aged
• Animals
• Breast Neoplasms (mortality, pathology)
• Cell Line, Tumor
• Cell Movement
• ErbB Receptors (metabolism)
• Female
• Genes, ras
• Humans
• Membrane Proteins (physiology)
• Mice
• Mice, Inbred BALB C
• Middle Aged
• Neoplasm Invasiveness
• Phosphatidylinositol 3-Kinases (physiology)
• Phosphorylation
• Proteomics
• Proto-Oncogene Proteins c-akt (physiology)
• Signal Transduction