Contribution of the R-Ras2 GTP-binding protein to primary breast tumorigenesis and late-stage metastatic disease

Larive, Romain M.; Moriggi, Giulia; Menacho‐Marquez, Mauricio; Cañamero, Marta; Álava, Enrique de; Alarcón, Balbino; Dosil, Mercedes; Bustelo, Xosé R.

doi:10.1038/ncomms4881

Cited by 31 publications

(28 citation statements)

References 49 publications

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“…Oncogenic mutations of Ras are important drivers of malignant behaviour within melanoma and pancreatic cancers, and although such activating mutations are relatively rare within breast cancer, overexpression of Ras mRNA and protein has been demonstrated [ 95 ]. Our data show a strong increase in transcript abundance for RRAS2 (Figure 3 ), consistent with reports that RRAS2 drives PI3K-dependent tumorigenesis and contributes to late stage metastasis in certain lung cancers [ 96 ]. Activation of Ras proteins by a range of growth factor receptors [ 97 ] leads to activation of the Raf-MEK-ERK [ 94 ] and the PI3K-Akt signal transduction cascades, culminating in the regulation of cellular survival and proliferation genes [ 90 , 98 ].…”

Section: Discussionsupporting

confidence: 92%

Stimulus-dependent differences in signalling regulate epithelial-mesenchymal plasticity and change the effects of drugs in breast cancer cell lines

et al. 2015

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Introduction: The normal process of epithelial mesenchymal transition (EMT) is subverted by carcinoma cells to facilitate metastatic spread. Cancer cells rarely undergo a full conversion to the mesenchymal phenotype, and instead adopt positions along the epithelial-mesenchymal axis, a propensity we refer to as epithelial mesenchymal plasticity (EMP). EMP is associated with increased risk of metastasis in breast cancer and consequent poor prognosis. Drivers towards the mesenchymal state in malignant cells include growth factor stimulation or exposure to hypoxic conditions.

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Section: Discussionsupporting

confidence: 92%

Stimulus-dependent differences in signalling regulate epithelial-mesenchymal plasticity and change the effects of drugs in breast cancer cell lines

et al. 2015

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“…We identified and validated three genes that can be directly activated by STAT3-GLI1 and/or STAT3-tGLI1 cooperation, namely, R-Ras2, Cep70, and UPF3A. R-Ras2 (also known as TC21) is a transforming GTPase that shares downstream effectors with Ras subfamily proteins 36 . Constitutively activated mutants of the Ras-related protein R-Ras2 has been shown to promote tumorigenic transformation of NIH3T3 cells 23 .…”

Section: Discussionmentioning

confidence: 99%

Interaction between STAT3 and GLI1/tGLI1 oncogenic transcription factors promotes the aggressiveness of triple-negative breast cancers and HER2-enriched breast cancer

Sirkisoon¹,

Carpenter²,

Rimkus³

et al. 2018

Oncogene

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STAT3, GLI1, and truncated GLI1 (tGLI1) are oncogenic transcription factors playing important roles in breast cancer. tGLI1 is a gain-of-function GLI1 isoform. Whether STAT3 physically and/or functionally interacts with GLI1/tGLI1 has not been explored. To address this knowledge gap, we analyzed 47 node-positive breast cancer specimens using immunohistochemical staining and found that p-STAT3 (Y705), GLI1, and tGLI1 are co-overexpressed in the majority of triple-negative (64%) and HER2-enriched (68%) breast carcinomas, and in lymph node metastases (65%). Using Gene Set Enrichment Analysis, we analyzed 710 breast tumors and found that STAT3- and GLI1/tGLI1-activation signatures are co-enriched in triple-negative and HER2-enriched, but not in luminal subtypes of breast cancers. Patients with high levels of STAT3 and GLI1/tGLI1 co-activation in their breast tumors had worse metastasis-free survival compared to those with low levels. Since these proteins co-overexpress in breast tumors, we examined whether they form complexes and observed that STAT3 interacted with both GLI1 and tGLI1. We further found that the STAT3-GLI1 and STAT3-tGLI1 complexes bind to both consensus GLI1- and STAT3-binding sites using chromatin immunoprecipitation (ChIP) assay, and that the co-overexpression markedly activated a promoter controlled by GLI1-binding sites. To identify genes that can be directly co-activated by STAT3 and GLI1/tGLI1, we analyzed three ChIP-Seq datasets and identified 36 potential target genes. Following validations using RT-PCR and survival analysis, we identified three genes as novel transcriptional targets of STAT3 and GLI1/tGLI1, R-Ras2, Cep70, and UPF3A. Finally, we observed that co-overexpression of STAT3 with GLI1/tGLI1 promoted the ability of breast cancer cells to form mammospheres and that STAT3 only cooperates with tGLI1 in immortalized mammary epithelial cells. In summary, our study identified novel physical and functional cooperation between two families of oncogenic transcription factors, and the interaction contributes to aggressiveness of breast cancer cells and poor prognosis of triple-negative and HER2-enriched breast cancers.

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“…We explore the role of the tumor microenvironment as a driver of FDG uptake in breast cancer cells using cultured cells and mouse tumor grafts. Both cell lines (mouse 4T1 and human MDA-MB-231 mammary adenocarcinoma) are considered models of late-stage metastatic breast cancer (25). In PET scans and autoradiography, these tumor grafts show reduced FDG signal in the core of the tumor ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Lactic Acid Accumulation in the Tumor Microenvironment Suppresses 18F-FDG Uptake

et al. 2019

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The process by which tumor cells take up 2-[ 18 F]fluoro-2deoxy-D-glucose (FDG) is heterogeneous and influenced by a multitude of factors. In mouse tumor grafts, the core of the tumor often presents lower FDG uptake than the periphery. Whether this pattern is caused by the intrinsic avidity of individual cells for FDG, the density of viable cells in the tumor, or the perfusion of the radiotracer remains unknown. In this study, we used radioluminescence microscopy to measure FDG uptake in single cells isolated from the core and periphery of the tumor and found that differences in FDG uptake persist on the level of single cells. Single cells from the core of 4T1 and MDA-MB-231 tumors grafts took up 26% to 84% less FDG than those from the periphery. These differences were observed in mice with large tumors (>8 mm diameter) but not in those with smaller tumors. To explain the origin of these differences, we examined the influence of three microenvironmental factors on FDG uptake. Hypoxia was ruled out as a possible explanation because its presence in the core would increase and not decrease FDG uptake. Higher cell proliferation in the periphery was consistent with higher FDG uptake, but there was no evidence of a causal relationship. Finally, lactate was higher in the core of the tumor, and it suppressed FDG uptake in a dose-dependent fashion. We therefore conclude that lactic acidosis-the combination of lactate ion buildup and acidic pH-can increase the heterogeneity of FDG uptake in MDA-MB-231 and 4T1 tumor grafts.Significance: Analysis of single cells from heterogeneous tumors reveals the role played by the tumor microenvironment, lactic acidosis in particular, on the uptake by tumor cells of 18 F-FDG, a PET imaging agent.

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Contribution of the R-Ras2 GTP-binding protein to primary breast tumorigenesis and late-stage metastatic disease

Cited by 31 publications

References 49 publications

Stimulus-dependent differences in signalling regulate epithelial-mesenchymal plasticity and change the effects of drugs in breast cancer cell lines

Stimulus-dependent differences in signalling regulate epithelial-mesenchymal plasticity and change the effects of drugs in breast cancer cell lines

Interaction between STAT3 and GLI1/tGLI1 oncogenic transcription factors promotes the aggressiveness of triple-negative breast cancers and HER2-enriched breast cancer

Lactic Acid Accumulation in the Tumor Microenvironment Suppresses 18F-FDG Uptake

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