Flotillin-2 deficiency leads to reduced lung metastases in a mouse breast cancer model
Flotillin-2 deficiency leads to reduced lung metastases in a mouse breast cancer model
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DOI：
10.1038/onc.2012.499
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发表时间：
2013-10-10
期刊：
影响因子：
8
通讯作者：
Mak, T. W.
中科院分区：
文献类型：
--
作者：
Berger, T.;Ueda, T.;Mak, T. W.
Flotillin 微结构域是细胞膜中的特殊脂筏结构域，可作为许多不同分子的物理平台，这些分子在关键的细胞内信号传导途径中很重要。 Flotillin-2 (Flot2) 与 flotillin-1 一起是不同于小凹脂筏的脂筏微区的标记物，并且与癌症的进展和转移形成有关。主要基于异种移植模型的研究，flotillin-2 与多种人类肿瘤（包括乳腺癌）的进展有关。在我们的研究中，我们在人类乳腺癌细胞系和乳腺肿瘤样本的高通量比较基因组杂交筛选中鉴定出flotillin-2 高度扩增。短发夹 RNA 介导的 flotillin-2 蛋白水平降低显着降低了人乳腺癌细胞系的体内致瘤性和转移能力。我们培育了缺乏 flotillin-2 的小鼠，并且还发现这些小鼠中 flotillin-1 蛋白水平降低，并且完全不存在 flotillin 特异性膜微结构域。为了研究 Flot2 在乳腺肿瘤发生和肺转移中的作用，我们使用体内分子遗传学方法，将已充分表征的乳腺癌转基因小鼠模型 MMTV-PyMT（小鼠乳腺肿瘤病毒-多瘤中 T 抗原）小鼠与基因靶向的 Flot2(-/-) 小鼠进行杂交。 Flotillin-2 缺乏导致观察到的肺转移数量显着减少，但对该模型中的原发性肿瘤形成没有影响。我们的结果表明，使用一种新颖的体内动物模型方法，Flot2 是乳腺肿瘤来源的肺转移的重要调节因子。
Flotillin microdomains, specialized lipid raft domains in cell membranes, serve as physical platforms for many different molecules important in crucial intracellular signaling pathways. Flotillin-2 (Flot2), together with flotillin-1, is a marker for lipid raft microdomains distinct from caveolar lipid rafts, and has been implicated in the progression of cancer and metastasis formation. Based largely on studies in xenograft models, flotillin-2 has been implicated in the progression of multiple types of human tumors, including breast cancer. In our studies, we identified flotillin-2 as highly amplified in a high-throughput comparative genomic hybridization screen of human breast cancer cell lines and breast tumor samples. Short hairpin RNA-mediated reduction of flotillin-2 protein levels significantly reduced the tumorigenicity and metastatic capability of a human breast cancer cell line in vivo. We generated mice deficient for flotillin-2 and also found a reduction of flotillin-1 protein levels and complete absence of flotillin-specific membrane microdomains in these mice. To examine the role of Flot2 in mammary tumorigenesis and lung metastasis, we used an in vivo molecular genetics approach, crossing a well-characterized transgenic mouse model of breast cancer, the MMTV-PyMT (mouse mammary tumor virus-polyoma middle T antigen) mouse, with gene-targeted Flot2(-/-) mice. Flotillin-2 deficiency lead to a striking reduction in the number of lung metastasis observed, but had no influence on primary tumor formation in this model. Our results indicate, using a novel in vivo animal model approach, that Flot2 is an important regulator of mammary tumor-derived lung metastasis.