Rab25 acts as an oncogene in luminal B breast cancer and is causally associated with Snail driven EMT.
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.
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Shreya
S
Mitra
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Lorenzo
L
Federico
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Wei
W
Zhao
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Jennifer
J
Dennison
Center for Statistical Bioinformatics, Texas A&M University, College Station, TX, USA.
Tapasree Roy
TR
Sarkar
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Fan
F
Zhang
Department of Radiation Oncology, University of Cincinnati, Cincinnati, OH, USA.
Vinita
V
Takiar
Cardiac Catheterization Laboratory, Michael and DeBakey Medical Center, Houston, TX, USA.
Kwai W
KW
Cheng
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA .
Sendurai
S
Mani
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Ju Seog
JS
Lee
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Gordon B
GB
Mills
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D062445:Claudin-1 / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D009857:Oncogenes; D010634:Phenobarbital / Q000737:chemistry; D011401:Promoter Regions, Genetic; D000071250:Snail Family Transcription Factors / Q000378:metabolism*; D014945:Wound Healing; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
C568108:CLDN1 protein, human; D062445:Claudin-1; C509763:Rab25 protein, human; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D020691:rab GTP-Binding Proteins; D010634:Phenobarbital
Rab coupling protein; Rab25; breast cancer; claudin low; luminal B