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

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.

MiR‐577 suppresses epithelial‐mesenchymal transition and metastasis of breast cancer by targeting Rab25

“…Mitra et al . showed that Rab25 acts as an oncogene in luminal B BC and is associated with snail‐driven EMT . Our results show that Rab25 influences the EMT‐related invasion of BC cells.…”

Credentialing Individual Samples for Proteogenomic Analysis

“…1A-1B), which is similar to the degree of correlation observed in our previous pan-cancer study of 11 tumor types (1). The median correlation of 146 cis total protein-mRNA pairs was 0.336, which is similar to the CPTAC breast, ovarian and bowel data (9,20,30). As expected, the 51 phosphorylated proteins assessed by RPPA showed much lower correlation with matched mRNAs (median Pearson's r ϭ 0.126).…”

Rab25 Acts as a Promising Novel Bio-Marker in the Prognosis of Patients with Hepatocellular Carcinoma

“…This result was accorded with the previous studies. A study of Mitra et al demonstrated that the mRNA and protein expression levels of Rab25 were signi cantly elevated in breast cancer cell lines [19]. In the study of Sheach et al, tissue microarray section showed the protein expression of Rab25 was higher in ovarian cancer [20].…”