Rho GEFs and Cancer: Linking Gene Expression and Metastatic Dissemination

Barrio-Real, Laura; Kazanietz, Marcelo G.

doi:10.1126/scisignal.2003543

Cited by 50 publications

(42 citation statements)

References 49 publications

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“…Surprisingly, we found that ECT2 is required for E6AP regulation of EGF-induced RhoA and Cdc42 activation but not Rac1 activation. As E6AP downregulation still increases Rac1 activity, other GEFs are likely to mediate Rac1 activation and indeed, others GEFs are highly expressed in human breast cancers (49). For example, the GEF Tiam1 is highly expressed in high-grade breast tumors, where it mediates migration and invasion (50,51).…”

Section: Discussionmentioning

confidence: 99%

The E3-ligase E6AP Represses Breast Cancer Metastasis via Regulation of ECT2-Rho Signaling

et al. 2016

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Metastatic disease is the major cause of breast cancer-related death and despite many advances, current therapies are rarely curative. Tumor cell migration and invasion require actin cytoskeletal reorganization to endow cells with capacity to disseminate and initiate the formation of secondary tumors. However, it is still unclear how these migratory cells colonize distant tissues to form macrometastases. The E6-associated protein, E6AP, acts both as an E3 ubiquitin-protein ligase and as a coactivator of steroid hormone receptors. We report that E6AP suppresses breast cancer invasiveness, colonization, and metastasis in mice, and in breast cancer patients, loss of E6AP associates with poor prognosis, particularly for basal breast cancer. E6AP regulates actin cytoskeletal remodeling via regulation of Rho GTPases, acting as a negative regulator of ECT2, a GEF required for activation of Rho GTPases. E6AP promotes ubiquitination and proteasomal degradation of ECT2 for which high expression predicts poor prognosis in breast cancer patients. We conclude that E6AP suppresses breast cancer metastasis by regulating actin cytoskeleton remodeling through the control of ECT2 and Rho GTPase activity. These findings establish E6AP as a novel suppressor of metastasis and provide a compelling rationale for inhibition of ECT2 as a therapeutic approach for patients with metastatic breast cancer.Cancer Res; 76(14); 4236-48. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 99%

The E3-ligase E6AP Represses Breast Cancer Metastasis via Regulation of ECT2-Rho Signaling

et al. 2016

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“…The remaining four genes VAV2 (VAV guanine nucleotide exchange factor 2), ASNS (asparagine synthesis), DNMT3B (DNA methyltransferase 3 beta), and AURKA (Aurora kinase A) not only all promote PC pathogenesis but also play a role in the development of CRPC (Gravina et al ., 2011; Magani et al ., 2017; Mosquera et al ., 2013; Sircar et al ., 2012). VAV2 is a coactivator of androgen receptor (AR) and sustains AR signaling under androgen deprivation therapy (ADT) (Magani et al ., 2017); it also promotes angiogenesis and metastasis (Barrio‐Real and Kazanietz, 2012). AURKA plays a critical role in mitosis (Dominguez‐Brauer et al ., 2015; Plotnikova et al ., 2015) and promotes the development of neuroendocrine PC under ADT (Beltran et al ., 2011; Mosquera et al ., 2013).…”

Section: Resultsmentioning

confidence: 99%

Construction of a set of novel and robust gene expression signatures predicting prostate cancer recurrence

Jiang

Mei

et al. 2018

Molecular Oncology

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We report here numerous novel genes and multiple new signatures which robustly predict prostate cancer (PC) recurrence. We extracted 696 differentially expressed genes relative to a reported PC signature from the TCGA dataset (n = 492) and built a 15‐gene signature (SigMuc1NW) using Elastic‐net with 10‐fold cross‐validation through analyzing their expressions at 1.5 standard deviation/SD below and 2 SD above a population mean. SigMuc1NW predicts biochemical recurrence (BCR) following surgery with 56.4% sensitivity, 72.6% specificity, and 63.24 median months disease free (MMDF) (P = 1.12e‐12). The prediction accuracy is improved with the use of SigMuc1NW's cutpoint (P = 3e‐15) and is further enhanced (sensitivity 67%, specificity 75.7%, MMDF 45.2, P = 0) when all 15 genes were analyzed through their cutpoints instead of their SDs. These genes individually associate with BCR using either SD or cutpoint as the cutoff points. Eight of 15 genes are individual risk factors after adjusting for age at diagnosis, Gleason score, surgical margin, and tumor stage. Eleven of 15 genes are novel to PC. SigMuc1NW discriminates BCR with time‐dependent AUC (tAUC) values of 76.6% at 11.5 months (76.6%–11.5 m), 73.8%‐22.3 m, 78.5%‐32.1 m, and 76.4%–48.4 m. SigMuc1NW is correlated with adverse features of PC, high Gleason scores (odds ratio/OR 1.48, P < 2e‐16), and advanced tumor stages (OR 1.33, P = 4.37e‐13). SigMuc1NW remains an independent risk factor of BCR (HR 2.44, 95% CI 1.53–3.87, P = 1.62e‐4) after adjusting for age at diagnosis, Gleason score, surgical margin, and tumor stage. In an independent PC (MSKCC) cohort (n = 140), these 15 genes were altered in PC vs normal tissue, metastatic PCs vs primary PCs, and recurrent PCs vs nonrecurrent PCs. Importantly, a 10‐gene subsignature SigMuc1NW1 predicts BCR in MSKCC (P = 3.11e‐15) and TCGA (P = 3.13e‐12); SigMuc1NW1 discriminates BCR at 18.4 m with tAUC as 82.5%. Collectively, our analyses support SigMuc1NW as a novel and robust signature in predicting BCR of PC.

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“…Interestingly, the role of Rho GEFS in cancer is emerging, including Vav2 (ref. 68). Moreover, Vav2 recently was shown to be required for lungspecific metastasis of breast cancer 69 .…”

Section: Discussionmentioning

confidence: 99%

Receptor tyrosine kinase c-Met controls the cytoskeleton from different endosomes via different pathways

2014

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Receptor tyrosine kinases (RTKs) are increasingly recognized as having the capacity to signal post-internalization. Signalling outputs and/or duration, and subsequent cellular outcome, are thought to be distinct when emanating from endosomes compared with those from the plasma membrane. Here we show, in invasive, basal-like human breast cell models, that different mechanisms are engaged by the RTK c-Met in two different endosomes to control the actin cytoskeleton via the key migratory signal output Rac1. Despite an acute activation of Rac1 from peripheral endosomes (PEs), c-Met needs to traffic to a perinuclear endosome (PNE) to sustain Rac1 signalling, trigger optimal membrane ruffling, cell migration and invasion. Unexpectedly, in the PNE but not in the PE, PI3K and the Rac-GEF Vav2 are required. Thus we describe a novel endosomal signalling mechanism whereby one signal output, Rac1, is stimulated through distinct pathways by the same RTK depending on which endosome it is localized to in the cell.

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Rho GEFs and Cancer: Linking Gene Expression and Metastatic Dissemination

Cited by 50 publications

References 49 publications

The E3-ligase E6AP Represses Breast Cancer Metastasis via Regulation of ECT2-Rho Signaling

The E3-ligase E6AP Represses Breast Cancer Metastasis via Regulation of ECT2-Rho Signaling

Construction of a set of novel and robust gene expression signatures predicting prostate cancer recurrence

Receptor tyrosine kinase c-Met controls the cytoskeleton from different endosomes via different pathways

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