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A novel role for flotillin‐1 in H ‐ R as‐regulated breast cancer aggressiveness
Author(s) -
Koh Minsoo,
Yong HaeYoung,
Kim EunSook,
Son Hwajin,
Jeon You Rim,
Hwang JinSun,
Kim MyeongOk,
Cha Yujin,
Choi Wahn Soo,
Noh DongYoung,
Lee KyungMin,
Kim KiBum,
Lee JaeSeon,
Kim Hyung Joon,
Kim Haemin,
Kim HongHee,
Kim Eun Joo,
Park So Yeon,
Kim Hoe Suk,
Moon Woo Kyung,
Choi Kim HyeongReh,
Moon Aree
Publication year - 2015
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.29869
Subject(s) - lipid raft , breast cancer , cancer research , triple negative breast cancer , gene knockdown , metastasis , cancer , biology , cell culture , chemistry , medicine , signal transduction , microbiology and biotechnology , genetics
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.