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.
Highlights
The vesicular trafficking machinery regulated by Rab GTPase decorated vesicles [1] optimizes spatiotemporal delivery of extracellular and intracellular cargo to cellular hotspots by triggering downstream cellular signaling that drives growth, locomotion [2], development [3] and overall survival of organisms [4, 5]
We have demonstrated that the Rab25 amplicon and Rab25 expression is associated with a worsened outcome in ovarian cancer and increased the aggressiveness of a subset of breast cancer cell lines [32, 33]
In this study we discovered that Rab25 is a context dependent oncogene with a potential role in breast cancer cell plasticity
Summary
The vesicular trafficking machinery regulated by Rab GTPase decorated vesicles [1] optimizes spatiotemporal delivery of extracellular and intracellular cargo to cellular hotspots by triggering downstream cellular signaling that drives growth, locomotion [2], development [3] and overall survival of organisms [4, 5]. Cancer cells frequently co-opt and corrupt mechanisms used by normal cells to increase robustness or to mediate events associated with tumorigenesis and progression. With aberrations in this complex multicomponent resource management and transportation machinery leading to a multitude of inherited and acquired disorders including cancer [14], Rab GTPase family members are emerging as exploitable targets for disease therapy [15,16,17]. We have demonstrated that the Rab amplicon and Rab expression is associated with a worsened outcome in ovarian cancer and increased the aggressiveness of a subset of breast cancer cell lines [32, 33]. The ambiguous role of Rab in cancer initiation, progression and prognosis [42], including its role in breast cancer progression [21, 42, 43] is confusing, conflicting, and poorly understood
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