Rab11-FIP1C Is a Critical Negative Regulator in ErbB2-Mediated Mammary Tumor Progression

Boulay, Pierre Luc; Mitchell, Louise; Turpin, Jason; Huot-Marchand, Julie Émilie; Lavoie, Cynthia; Sanguin-Gendreau, Virginie; Jones, Laura M.; Mitra, Sugata; Livingstone, Julie; Campbell, Shirley; Hallett, Michael; Mills, Gordon B.; Park, Morag; Chodosh, Lewis A.; Strathdee, Douglas; Norman, Jim C.; Muller, William J.

doi:10.1158/0008-5472.can-15-2782

Cited by 31 publications

(25 citation statements)

References 41 publications

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“…But new evidence highlights a tumor suppressor role in ERB2 driven breast cancers [61]. This led us to opt for a coordinate analysis of RCP and Rab25 within the luminal B patient subgroup to evaluate if our in vitro observations translate in patients.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2016

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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.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2016

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“…29 RAB3D was also discovered to promote the CDK4 and CDK6 signaling, thereby stimulating cell cycle progression and ultimately leading to the proliferation of tumor cells. 30,31 In our future research, we will work to study the effects of RAB3D on NSCLCassociated classical signaling pathways. Of course, there are limitations to this research.…”

Section: Discussionmentioning

confidence: 99%

<p>CircRNA hsa_circ_0087862 Acts as an Oncogene in Non-Small Cell Lung Cancer by Targeting miR-1253/RAB3D Axis</p>

Wan

Xiong

et al. 2020

OTT

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Purpose: Circular RNAs (circRNAs) have been found to regulate several human tumors. The present study was to explore the mechanism of hsa_circ_0087862 in regulating nonsmall cell lung cancer (NSCLC). Methods: Totally 102 NSCLC cases were enrolled. NCI-H1359 and A549 cells were transfected. Cells viability, apoptosis, migration and invasion were determined by CCK-8 assay, flow cytometry, scratch test and transwell experiment, respectively. Luciferase reporter gene assay and RNA immunoprecipitation (RIP) assay were performed. Xenograft tumor experiments were performed using nude mice. hsa_circ_0087862, miR-1253 and RAB3D expression in tissues/cells were detected by qRT-PCR. RAB3D and Ki67 protein expressions in cells/tissues were researched by Western blot and immunohistochemistry. Apoptosis of xenograft tumor tissue cells was detected using Tunel assay. Results: hsa_circ_0087862 was significantly up-regulated in NSCLC patients, which was associated with poor prognosis (P < 0.05). hsa_circ_0087862 down-regulation prominently weakened NSCLC cells viability, migration, invasion and enhanced apoptosis (P < 0.01). hsa_circ_0087862 overexpression exhibited the opposite results in NSCLC cells. miR-1253 was sponged by hsa_circ_0087862. miR-1253 expression in NSCLC tissues was negatively correlated with hsa_circ_0087862 (P < 0.001). RAB3D expression in NSCLC was directly inhibited by miR-1253. miR-1253 down-regulation or RAB3D overexpression dramatically reversed NSCLC cells phenotype induced by hsa_circ_0087862 down-regulation. hsa_circ_0087862 down-regulation markedly inhibited tumor growth in vivo (P < 0.01). In xenograft tumor tissues, hsa_circ_0087862 down-regulation obviously decreased expression of RAB3D, Ki67 and increased apoptosis. Conclusion: hsa_circ_0087862 acted as an oncogene in NSCLC by targeting miR-1253/ RAB3D.

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“…This is achieved by two mechanisms: either mutated RTKs hijack the endocytic apparatus, which, in turn, fosters their signaling properties, or altered endocytic/trafficking genes potentiate the duration and the amplitude of the signal (Sigismund et al, 2012). Indeed, alterations in the balance between receptor recycling and degradation have been found in several aggressive cancers (Belle et al, 2015;Boulay et al, 2016). This latter mechanism largely relies on the overexpression and amplification of genes that are involved in RTKs endocytosis and recycling, including several GTPases belonging to the Rab family which control vesicular trafficking (Caswell et al, 2007;Cheng et al, 2004;Frittoli et al, 2014;Kajiho et al, 2016;Wheeler et al, 2015).…”

Section: Egfr Cancer Mutants Divert From the Normal Trafficking Itinementioning

confidence: 99%

Emerging functions of the EGFR in cancer

2017

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The physiological function of the epidermal growth factor receptor (EGFR) is to regulate epithelial tissue development and homeostasis. In pathological settings, mostly in lung and breast cancer and in glioblastoma, the EGFR is a driver of tumorigenesis. Inappropriate activation of the EGFR in cancer mainly results from amplification and point mutations at the genomic locus, but transcriptional upregulation or ligand overproduction due to autocrine/paracrine mechanisms has also been described. Moreover, the EGFR is increasingly recognized as a biomarker of resistance in tumors, as its amplification or secondary mutations have been found to arise under drug pressure. This evidence, in addition to the prominent function that this receptor plays in normal epithelia, has prompted intense investigations into the role of the EGFR both at physiological and at pathological level. Despite the large body of knowledge obtained over the last two decades, previously unrecognized (herein defined as ‘noncanonical’) functions of the EGFR are currently emerging. Here, we will initially review the canonical ligand‐induced EGFR signaling pathway, with particular emphasis to its regulation by endocytosis and subversion in human tumors. We will then focus on the most recent advances in uncovering noncanonical EGFR functions in stress‐induced trafficking, autophagy, and energy metabolism, with a perspective on future therapeutic applications.

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Rab11-FIP1C Is a Critical Negative Regulator in ErbB2-Mediated Mammary Tumor Progression

Cited by 31 publications

References 41 publications

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

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

<p>CircRNA hsa_circ_0087862 Acts as an Oncogene in Non-Small Cell Lung Cancer by Targeting miR-1253/RAB3D Axis</p>

Emerging functions of the EGFR in cancer

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