Rab25 acts as an oncogene in luminal B breast cancer and is causally associated with Snail driven EMT

// Shreya Mitra 1 , Lorenzo Federico 1 , Wei Zhao 1 , Jennifer Dennison 1 , Tapasree Roy Sarkar 2 , Fan Zhang 1 , Vinita Takiar 3 , Kwai W. Cheng 4 , Sendurai Mani 5 , Ju Seog Lee 1 , Gordon B. Mills 1 1 Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Center for Statistical Bioinformatics, Texas A&M University, College Station, TX, USA 3 Department of Radiation Oncology, University of Cincinnati, Cincinnati, OH, USA 4 Cardiac Catheterization Laboratory, Michael and DeBakey Medical Center, Houston, TX, USA 5 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Correspondence to: Shreya Mitra, email: smitra@mdanderson.org Keywords: Rab25, Rab coupling protein, breast cancer, luminal B, claudin low Received: March 30, 2016 Accepted: May 10, 2016 Published: May 31, 2016 ABSTRACT 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.