Tyrosine phosphatase SHP2 increases cell motility in triple-negative breast cancer through the activation of SRC-family kinases

Sausgruber, Nina; Coissieux, Marie–May; Britschgi, Adrian; Wyckoff, Jeffrey; Aceto, Nicola; Leroy, Cédric; Mb, Stadler; Voshol, Hans; Bonenfant, Débora; Bentires‐Alj, Mohamed

doi:10.1038/onc.2014.170

Cited by 58 publications

(54 citation statements)

References 28 publications

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“…17 Still, in most other solid tumors examined, including breast cancer, lung cancer and neuroblastoma, Shp2 is generally considered to be an oncoprotein, promoting mitogenic and 1 survival signaling. [18][19][20][21] Furthermore, emerging evidence suggests that Shp2 facilitates migration, invasion and metastasis of breast cancer cells by modulating focal adhesion kinase (FAK) or Fyn downstream of growth factors or integrins. [22][23][24][25] A recent study by Yang et al 26 provides evidence that Gab1 binds to PAR1 and enhances PAR3 phosphorylation by PAR1, and serves as a negative regulator of epithelial TJ formation and cell polarity.…”

Section: Introductionmentioning

confidence: 99%

Shp2 promotes metastasis of prostate cancer by attenuating the PAR3/PAR6/aPKC polarity protein complex and enhancing epithelial-to-mesenchymal transition

Zhang

Zhao

et al. 2015

Oncogene

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Epithelial-to-mesenchymal transition (EMT), marked by the dissolution of cell-cell junctions, loss of cell polarity and increased cell motility, is one of the essential steps for prostate cancer metastasis. However, the underlying mechanism has not been fully explored. We report in this study that Shp2 is upregulated in prostate cancers and is associated with a poor disease outcome, namely tumor metastasis and shortened patient survival. Overexpression of wild-type Shp2 or an oncogenic Shp2 mutant leads to increased prostate cancer cell proliferation, colony and sphere formation, and in vivo tumor formation. Opposite effects are seen in Shp2-knockdown cells. Moreover, Shp2 promotes in vitro migration and in vivo metastasis of prostatic tumor cells. Mechanistically, Shp2 interacts with PAR3 (partitioning-defective 3) via its Src homology-2 domain. Ectopic expression of Shp2 attenuates the phosphorylation of PAR3 and the formation of the PAR3/PAR6/atypical protein kinase C polarity protein complex, resulting in disrupted cell polarity, dysregulated cell-cell junctions and increased EMT. These findings provide a novel mechanism by which oncogenic signal-transduction molecules regulate cell polarity and induction of EMT.

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Section: Introductionmentioning

confidence: 99%

Shp2 promotes metastasis of prostate cancer by attenuating the PAR3/PAR6/aPKC polarity protein complex and enhancing epithelial-to-mesenchymal transition

Zhang

Zhao

et al. 2015

Oncogene

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“…Peptides were analyzed by LC-MS/MS (LTQ OrbiTrap Elite; Thermo) as described previously (14), using spectral counting as a proxy for the protein quantity.…”

Section: Proteomicsmentioning

confidence: 99%

Maximizing the Efficacy of MAPK-Targeted Treatment inPTENLOF/BRAFMUT Melanoma through PI3K and IGF1R Inhibition

et al. 2016

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The introduction of MAPK pathway inhibitors paved the road for significant advancements in the treatment of BRAF-mutant (BRAFMUT) melanoma. However, even BRAF/MEK inhibitor combination therapy has failed to offer a curative treatment option, most likely because these pathways constitute a codependent signaling network. Concomitant PTEN loss of function (PTENLOF) occurs in approximately 40% of BRAFMUT melanomas. In this study, we sought to identify the nodes of the PTEN/PI3K pathway that would be amenable to combined therapy with MAPK pathway inhibitors for the treatment of PTENLOF/BRAFMUT melanoma. Large-scale compound sensitivity profiling revealed that PTENLOF melanoma cell lines were sensitive to PI3Kβ inhibitors, albeit only partially. An unbiased shRNA screen (7,500 genes and 20 shRNAs/genes) across 11 cell lines in the presence of a PI3Kβ inhibitor identified an adaptive response involving the IGF1R–PI3Kα axis. Combined inhibition of the MAPK pathway, PI3Kβ, and PI3Kα or insulin-like growth factor receptor 1 (IGF1R) synergistically sustained pathway blockade, induced apoptosis, and inhibited tumor growth in PTENLOF/BRAFMUT melanoma models. Notably, combined treatment with the IGF1R inhibitor, but not the PI3Kα inhibitor, failed to elevate glucose or insulin signaling. Taken together, our findings provide a strong rationale for testing combinations of panPI3K, PI3Kβ + IGF1R, and MAPK pathway inhibitors in PTENLOF/BRAFMUT melanoma patients to achieve maximal response. Cancer Res; 76(2); 390–402. ©2015 AACR.

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“…With respect to several top genes, like PTPN11 , it encodes the protein-tyrosine phosphatase SHP2 whose protein expression was significantly increased in human thyroid carcinoma [30]. In addition, there are literatures suggesting that somatic gain-of-function mutations of PTPN11 are presented in breast cancer [30, 31], lung adenocarcinomas [32] and etc. BRAF is ranked as the second impactful driver gene which is an important event in the development of papillary thyroid cancer [33].…”

Section: Resultsmentioning

confidence: 99%

LNDriver: identifying driver genes by integrating mutation and expression data based on gene-gene interaction network

et al. 2016

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BackgroundCancer is a complex disease which is characterized by the accumulation of genetic alterations during the patient’s lifetime. With the development of the next-generation sequencing technology, multiple omics data, such as cancer genomic, epigenomic and transcriptomic data etc., can be measured from each individual. Correspondingly, one of the key challenges is to pinpoint functional driver mutations or pathways, which contributes to tumorigenesis, from millions of functional neutral passenger mutations.ResultsIn this paper, in order to identify driver genes effectively, we applied a generalized additive model to mutation profiles to filter genes with long length and constructed a new gene-gene interaction network. Then we integrated the mutation data and expression data into the gene-gene interaction network. Lastly, greedy algorithm was used to prioritize candidate driver genes from the integrated data. We named the proposed method Length-Net-Driver (LNDriver).ConclusionsExperiments on three TCGA datasets, i.e., head and neck squamous cell carcinoma, kidney renal clear cell carcinoma and thyroid carcinoma, demonstrated that the proposed method was effective. Also, it can identify not only frequently mutated drivers, but also rare candidate driver genes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-016-1332-y) contains supplementary material, which is available to authorized users.

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Tyrosine phosphatase SHP2 increases cell motility in triple-negative breast cancer through the activation of SRC-family kinases

Cited by 58 publications

References 28 publications

Shp2 promotes metastasis of prostate cancer by attenuating the PAR3/PAR6/aPKC polarity protein complex and enhancing epithelial-to-mesenchymal transition

Shp2 promotes metastasis of prostate cancer by attenuating the PAR3/PAR6/aPKC polarity protein complex and enhancing epithelial-to-mesenchymal transition

Maximizing the Efficacy of MAPK-Targeted Treatment inPTENLOF/BRAFMUT Melanoma through PI3K and IGF1R Inhibition

LNDriver: identifying driver genes by integrating mutation and expression data based on gene-gene interaction network

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