Mitra Shreya, Federico Lorenzo, Zhao Wei, Dennison Jennifer, Sarkar Tapasree Roy, Zhang Fan, Takiar Vinita, Cheng Kwai W, Mani Sendurai, Lee Ju Seog, Mills Gordon B
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Center for Statistical Bioinformatics, Texas A&M University, College Station, TX, USA.
Oncotarget. 2016 Jun 28;7(26):40252-40265. doi: 10.18632/oncotarget.9730.
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.
Rab GTPases调节囊泡运输机制，该机制可将包括生长因子受体、整合素、营养受体和连接蛋白在内的多种货物运输并递送至特定的细胞内位点。囊泡运输机制确实是一种主要的翻译后修饰因子，对细胞内稳态至关重要。这种严格控制系统的失调会导致包括癌症在内的多种疾病。在此我们证明，Rab25作为一种关键的GTPase，主要定位于顶端回收内体，在雌激素受体阳性（ER+ve）细胞系中的mRNA和蛋白表达较高，是乳腺癌细胞系中的一个二分变量。Rab25及其效应器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在基底样乳腺癌中的水平降低，在claudin-low肿瘤中几乎完全缺失。尽管存在包含Rab25的1q扩增子，但这种二分法在所有乳腺癌亚型中都存在，这可能是由于Rab25启动子的甲基化差异所致。在功能上，Rab25水平升高会驱动癌症的主要特征，包括无限生长和转移，但仅在管腔B型乳腺癌中如此。重要的是，在这种ER+ve肿瘤中，Rab25及其效应器RCP的共表达与明显恶化的临床结果显著相关。重要的是，在claudin-low细胞系中，外源性Rab25显著抑制细胞迁移。同样，在Snail诱导的上皮-间质转化（EMT）过程中，外源性Rab25有力地逆转了Snail驱动的侵袭。总体而言，本研究证实了Rab25在乳腺癌中具有显著的背景依赖性作用，其中Rab25在管腔B型癌症中扩增并增强侵袭性，而在claudin-low肿瘤中，Rab25缺失，表明可能具有抗肿瘤功能。
