Rab25 acts as an oncogene in luminal B breast cancer and is causally associated with Snail driven EMT.
Rab25 acts as an oncogene in luminal B breast cancer and is causally associated with Snail driven EMT.
复制标题
DOI：
10.18632/oncotarget.9730
复制
发表时间：
2016-06-28
期刊：
影响因子：
--
通讯作者：
Mills GB
中科院分区：
文献类型：
--
作者：
Mitra S;Federico L;Zhao W;Dennison J;Sarkar TR;Zhang F;Takiar V;Cheng KW;Mani S;Lee JS;Mills GB
Rab GTP酶调节囊泡运输机制，其运输和递送多种货物，包括生长因子受体、整联蛋白、营养受体和连接蛋白至特定的细胞内位点。运输机制确实是一个主要的翻译后修饰剂，对细胞内稳态至关重要。这种严格控制的系统的失调导致包括癌症在内的广泛的疾病。在本文中，我们证明Rab25，一个关键的GT3，主要装饰顶端再循环内体，是乳腺癌细胞系中的二分变量，在雌激素受体阳性（ER+ve）细胞系中具有较高的mRNA和蛋白表达。Rab25及其效应物Rab偶联蛋白（RCP）在ER+ve乳腺癌中经常共同扩增并协同升高。相比之下，Rab25水平在基底样肿瘤中降低，并且在紧密连接蛋白低的肿瘤中几乎完全丧失。尽管存在跨乳腺癌亚型的Rab25宿主的1q扩增子，但这种二分法仍然存在，并且可能是由于Rab25启动子的差异甲基化。在功能上，Rab25水平升高驱动癌症的主要标志，包括不确定的生长和转移，但仅在管腔型B乳腺癌的情况下。重要的是，在这样的ER+ve肿瘤中，Rab25及其效应物RCP的共表达与显著恶化的临床结果显著相关。重要的是，在claudin低细胞系中，外源性Rab25显著抑制细胞迁移。类似地，在蜗牛诱导的上皮向间质转化（EMT）期间，外源性Rab25有力地逆转蜗牛驱动的侵袭。总体而言，该研究证实了Rab25在乳腺癌中的显著背景依赖性作用，其中Rab25在管腔B癌中扩增并增强侵袭性，而在紧密连接蛋白低的肿瘤中，Rab25丢失，表明可能的抗肿瘤功能。
The Rab GTPases regulate vesicular trafficking machinery that transports and delivers a diverse pool of cargo, including growth factor receptors, integrins, nutrient receptors and junction proteins to specific intracellular sites. The trafficking machinery is indeed a major posttranslational modifier and is critical for cellular homeostasis. Deregulation of this stringently controlled system leads to a wide spectrum of disorders including cancer. Herein we demonstrate that Rab25, a key GTPase, mostly decorating the apical recycling endosome, is a dichotomous variable in breast cancer cell lines with higher mRNA and protein expression in Estrogen Receptor positive (ER+ve) lines. Rab25 and its effector, Rab Coupling Protein (RCP) are frequently coamplified and coordinately elevated in ER+ve breast cancers. In contrast, Rab25 levels are decreased in basal-like and almost completely lost in claudin-low tumors. This dichotomy exists despite the presence of the 1q amplicon that hosts Rab25 across breast cancer subtypes and is likely due to differential methylation of the Rab25 promoter. Functionally, elevated levels of Rab25 drive major hallmarks of cancer including indefinite growth and metastasis but in case of luminal B breast cancer only. Importantly, in such ER+ve tumors, coexpression of Rab25 and its effector, RCP is significantly associated with a markedly worsened clinical outcome. Importantly, in claudin-low cell lines, exogenous Rab25 markedly inhibits cell migration. Similarly, during Snail-induced epithelial to mesenchymal transition (EMT) exogenous Rab25 potently reverses Snail-driven invasion. Overall, this study substantiates a striking context dependent role of Rab25 in breast cancer where Rab25 is amplified and enhances aggressiveness in luminal B cancers while in claudin-low tumors, Rab25 is lost indicating possible anti-tumor functions.
登录
查看更多内容
影响因子：
--
作者：
Kessler, Daniel;Gruen, Gianna-Carina;Jendrossek, Verena
通讯作者：
Jendrossek, Verena
关于癌症基因组地图集的泛伴奏蛋白质组学观点。
影响因子：
16.6
作者：
Akbani, Rehan;Ng, Patrick Kwok Shing;Werner, Henrica M. J.;Shahmoradgoli, Maria;Zhang, Fan;Ju, Zhenlin;Liu, Wenbin;Yang, Ji-Yeon;Yoshihara, Kosuke;Li, Jun;Ling, Shiyun;Seviour, Elena G.;Ram, Prahlad T.;Minna, John D.;Diao, Lixia;Tong, Pan;Heymach, John V.;Hill, Steven M.;Dondelinger, Frank;Stadler, Nicolas;Byers, Lauren A.;Meric-Bernstam, Funda;Weinstein, John N.;Broom, Bradley M.;Verhaak, Roeland G. W.;Liang, Han;Mukherjee, Sach;Lu, Yiling;Mills, Gordon B.
通讯作者：
Mills, Gordon B.
影响因子：
8.8
作者：
通讯作者：
--
影响因子：
3.3
作者：
Brewster, A. M.;Thompson, P.;Bondy, M.
通讯作者：
Bondy, M.
影响因子：
11.8
作者：
Dozynkiewicz, Marta A.;Jamieson, Nigel B.;MacPherson, Iain;Grindlay, Joan;van den Berghe, Peter V. E.;von Thun, Anne;Morton, Jennifer P.;Gourley, Charlie;Timpson, Paul;Nixon, Colin;McKay, Colin J.;Carter, Ross;Strachan, David;Anderson, Kurt;Sansom, Owen J.;Caswell, Patrick T.;Norman, Jim C.
通讯作者：
Norman, Jim C.