title: 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.affiliation: College of Pharmacy, Duksung Women's University, Seoul, Korea.
authors.forename: Minsoo
authors.initials: M
authors.lastname: Koh
authors.affiliation: College of Pharmacy, Duksung Women's University, Seoul, Korea.
authors.forename: Hae-Young
authors.initials: HY
authors.lastname: Yong
authors.affiliation: College of Pharmacy, Duksung Women's University, Seoul, Korea.
authors.forename: Eun-Sook
authors.initials: ES
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Duksung Women's University, Seoul, Korea.
authors.forename: Hwajin
authors.initials: H
authors.lastname: Son
authors.affiliation: College of Pharmacy, Duksung Women's University, Seoul, Korea.
authors.forename: You Rim
authors.initials: YR
authors.lastname: Jeon
authors.affiliation: College of Pharmacy, Duksung Women's University, Seoul, Korea.
authors.forename: Jin-Sun
authors.initials: JS
authors.lastname: Hwang
authors.affiliation: College of Pharmacy, Duksung Women's University, Seoul, Korea.
authors.forename: Myeong-Ok
authors.initials: MO
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Duksung Women's University, Seoul, Korea.
authors.forename: Yujin
authors.initials: Y
authors.lastname: Cha
authors.affiliation: Department of Immunology, School of Medicine, Konkuk University, Chungju, Korea.
authors.forename: Wahn Soo
authors.initials: WS
authors.lastname: Choi
authors.affiliation: Department of Surgery and Cancer Research Institute, College of Medicine, Seoul National University, Seoul, Korea.
authors.forename: Dong-Young
authors.initials: DY
authors.lastname: Noh
authors.affiliation: Department of Surgery and Cancer Research Institute, College of Medicine, Seoul National University, Seoul, Korea.
authors.forename: Kyung-Min
authors.initials: KM
authors.lastname: Lee
authors.affiliation: Department of Molecular Medicine, College of Medicine, Inha University, Incheon, Korea.
authors.forename: Ki-Bum
authors.initials: KB
authors.lastname: Kim
authors.affiliation: Department of Molecular Medicine, College of Medicine, Inha University, Incheon, Korea.
authors.forename: Jae-Seon
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Oral Physiology, School of Dentistry, Pusan National University, Yangsan, Korea.
authors.forename: Hyung Joon
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Cell and Developmental Biology, BK21 Program and Dental Research Institute, Seoul National University, Seoul, Korea.
authors.forename: Haemin
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Cell and Developmental Biology, BK21 Program and Dental Research Institute, Seoul National University, Seoul, Korea.
authors.forename: Hong-Hee
authors.initials: HH
authors.lastname: Kim
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
authors.forename: Eun Joo
authors.initials: EJ
authors.lastname: Kim
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
authors.forename: So Yeon
authors.initials: SY
authors.lastname: Park
authors.affiliation: Department of Radiology, Seoul National University Hospital, Seoul, Korea.
authors.forename: Hoe Suk
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Radiology, Seoul National University Hospital, Seoul, Korea.
authors.forename: Woo Kyung
authors.initials: WK
authors.lastname: Moon
authors.affiliation: Department of Pathology, Wayne State University School of Medicine, Detroit, MI.
authors.forename: Hyeong-Reh
authors.initials: HR
authors.lastname: Choi Kim
authors.affiliation: College of Pharmacy, Duksung Women's University, Seoul, Korea.
authors.forename: Aree
authors.initials: A
authors.lastname: Moon
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001943:Breast Neoplasms / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D011905:Genes, ras; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D040901:Proteomics; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D015398:Signal Transduction
chemical_list: D008565:Membrane Proteins; C106354:flotillins; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt
keywords: H-Ras; flotillin-1; invasion; lipid raft; triple-negative breast cancer