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Shp2 Signaling Suppresses Senescence in PyMT-induced Mammary Gland Cancer in Mice

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

ORGANISM(S): Mus musculus

SUBMITTER: Linxiang Lan

PROVIDER: E-GEOD-50518 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Shp2 signaling suppresses senescence in PyMT-induced mammary gland cancer in mice.

Lan Linxiang L Holland Jane D JD Qi Jingjing J Grosskopf Stefanie S Rademann Jörg J Vogel Regina R Györffy Balázs B Wulf-Goldenberg Annika A Birchmeier Walter W

The EMBO journal 20150303 11

In this study, we have used techniques from cell biology, biochemistry, and genetics to investigate the role of the tyrosine phosphatase Shp2 in tumor cells of MMTV-PyMT mouse mammary glands. Genetic ablation or pharmacological inhibition of Shp2 induces senescence, as determined by the activation of senescence-associated β-gal (SA-β-gal), cyclin-dependent kinase inhibitor 1B (p27), p53, and histone 3 trimethylated lysine 9 (H3K9me3). Senescence induction leads to the inhibition of self-renewal ...[more]

PMID: 25736378

Similar Datasets

Shp2 Signaling Suppresses Senescence in PyMT-induced Mammary Gland Cancer in Mice [Mouse430A_2 array]

Project description:In this study, we have used techniques from cell biology, biochemistry, and genetics to investigate the role of the tyrosine phosphatase Shp2 in tumor cells of MMTV-PyMT mouse mammary glands. Genetic ablation or pharmacological inhibition of Shp2 induces senescence, as determined by the activation of senescence-associated β-gal (SA-β-gal), cyclin-dependent kinase inhibitor 1B (p27), p53, and histone 3 trimethylated lysine 9 (H3K9me3). Senescence induction leads to inhibition of self-renewal of tumor cells and blockage of tumor formation and growth. A signaling cascade was identified that acts downstream of Shp2 to counter senescence: Src, Focal adhesion kinase and Map kinase inhibit senescence by activating the expression of S-phase kinase-associated protein 2 (Skp2), Aurora kinase A (Aurka), and the Notch ligand Delta-like 1 (Dll1), which block p27 and p53. Remarkably, the expression of Shp2 and of selected target genes predicts human breast cancer outcome. We conclude that therapies which rely on senescence induction by inhibiting Shp2 or controlling its target gene products may be useful in blocking breast cancer. For Shp2 ablation, primary mammary tumor cells from MMTV-PyMT;Shp2fl/fl mice were transduced with retroviruses expressing control GFP or CreERT2-GFP, and GFP-positive cells were purified by FACS and cultured as mammospheres for 1 week. Mammospheres were then treated with 50 nM 4-OHT for 2 hours, cultured for another 5 days, and subjected to RNA isolation. For pharmacological inhibition, primary mammary tumor cells from the same mice were cultured as mammospheres for 10 days and then treated with the Shp2 inhibitor GS493 for another 2 days. Mammospheres were then subjected to RNA isolation. Each group contains 3 replicates.

2015-03-06 | E-GEOD-50516 | biostudies-arrayexpress

Shp2 Signaling Suppresses Senescence in PyMT-induced Mammary Gland Cancer in Mice [Mouse430_2 array]

Project description:In this study, we have used techniques from cell biology, biochemistry, and genetics to investigate the role of the tyrosine phosphatase Shp2 in tumor cells of MMTV-PyMT mouse mammary glands. Genetic ablation or pharmacological inhibition of Shp2 induces senescence, as determined by the activation of senescence-associated ?-gal (SA-?-gal), cyclin-dependent kinase inhibitor 1B (p27), p53, and histone 3 trimethylated lysine 9 (H3K9me3). Senescence induction leads to inhibition of self-renewal of tumor cells and blockage of tumor formation and growth. A signaling cascade was identified that acts downstream of Shp2 to counter senescence: Src, Focal adhesion kinase and Map kinase inhibit senescence by activating the expression of S-phase kinase-associated protein 2 (Skp2), Aurora kinase A (Aurka), and the Notch ligand Delta-like 1 (Dll1), which block p27 and p53. Remarkably, the expression of Shp2 and of selected target genes predicts human breast cancer outcome. We conclude that therapies which rely on senescence induction by inhibiting Shp2 or controlling its target gene products may be useful in blocking breast cancer. Primary mammary tumor cells from MMTV-PyMT mice were cultured as mammospheres for 10 days and then treated with specific inhibitors of Notch (DAPT), MEK1 (U0126), FAK (TAE226), or Src (PP2) for another 2 days. Mammospheres were then subjected to RNA isolation. Each group contains 3 replicates.

2015-03-06 | E-GEOD-50517 | biostudies-arrayexpress

BT474 tumors and MCF10A-HER2/3 cells in the presence or absence of SHP2

Project description:This SuperSeries is composed of the following subset Series: GSE34523: BT474 tumors in the presence or absence of SHP2 GSE34524: MCF10A-HER2/3 cells grown in 3D cultures in the presence or absence of SHP2 Refer to individual Series

2011-12-20 | E-GEOD-34525 | biostudies-arrayexpress

Shp2 transcriptome in melanoma

Project description:1205Lu Metastatic Human melanoma cell lines with knockdown of Shp2 (PTPN11) were grown as xenograft tumors in NSG mice. RNA was extracted from the tumors and analyzed on [HuGene-2_0-st] Affymetrix Human Gene 2.0 ST Array [transcript (gene) version] Shp2 knockdown compared with non-target controls

2016-07-03 | E-GEOD-53282 | biostudies-arrayexpress

MCF10A-HER2/3 cells grown in 3D cultures in the presence or absence of SHP2

Project description:The first bona fide PTP proto-oncogene was the Src-homology 2 domain-containing phosphatase SHP2 (encoded by PTPN11), an ubiquitously expressed PTP that transduces mitogenic, pro-survival, cell fate and/or pro-migratory signals from numerous growth factor-, cytokine- and extracellular matrix receptors. In malignancies, SHP2 is hyperactivated either downstream of oncoproteins or by mutations.We provide analysis of the mammary epithelial cells MCF10A overexpressing human HER2 and HER3 and grown in 3D cultures for 15 days in the presence or absence of SHP2. The human mammary epithelial cells MCF10A were transduced with a doxycycline-inducible lentiviral vector expressing a CTRL miR or SHP2 miR1 or SHP2 miR2. Cells from each group were grown in 3D cultures, and the knockdown of SHP2 was induced for 15 days. RNA was extracted for gene expression analysis.

2011-12-20 | E-GEOD-34524 | biostudies-arrayexpress

Systematic Identification of SHP2 Phosphatase Substrates

Project description:Phosphatases play essential roles in normal cell physiology and diseases like cancer. The challenges of studying phosphatases have limited our understanding of their substrates, molecular mechanisms, and unique functions within highly complicate networks. Here we introduce a novel strategy using substrate trapping mutant coupled with quantitative mass spectrometry to identify physiological substrates of protein tyrosine phosphatase Src homology 2 containing protein tyrosine phosphatase 2 (SHP2) in a high-throughput manner. SHP2 plays a critical role in numerous cellular processes through the regulation of various signaling pathways. The method integrates three separate MS-based experiments; in vitro dephosphorylation assay, in vivo global phosphoproteomics, and pull down of substrate trapping mutant complex using HEK293SHP2KO cells. PTPN11-C459S/D425A is an optimized substrate trap mutant of SHP2. We identified eleven direct substrates, including both known and novel SHP2 substrates in EGFR signaling pathways, among which docking protein 1 (DOK1) was further validated as a new SHP2 substrate. This advanced workflow significantly improves the systemic identification of direct substrates of phosphatase, facilitating the comprehension of equally important roles of phosphatase signaling.

2022-09-20 | PXD028404 | Pride

BT474 tumors in the presence or absence of SHP2

Project description:The first bona fide PTP proto-oncogene was the Src-homology 2 domain-containing phosphatase SHP2 (encoded by PTPN11), an ubiquitously expressed PTP that transduces mitogenic, pro-survival, cell fate and/or pro-migratory signals from numerous growth factor-, cytokine- and extracellular matrix receptors. In malignancies, SHP2 is hyperactivated either downstream of oncoproteins or by mutations.We provide analysis of the breast cancer cells BT474 grown as xenografts in the presence or absence of SHP2 for 30 days. The HER2-postive breast cancer cell line BT474 was transduced with a doxycycline-inducible lentiviral vector expressing a CTRL miR or SHP2 miR1 or SHP2 miR2. Cells from each group were injected in imuunodeficinet mice and after tumor development, the knockdown of SHP2 was induced for 30 days in vivo. At day 30, tumors were dissected and RNA isolated for gene expression analysis.

2011-12-20 | E-GEOD-34523 | biostudies-arrayexpress

Primary TNBC tumor in the presence or absence of SHP2

Project description:The first bona fide PTP proto-oncogene was the Src-homology 2 domain-containing phosphatase SHP2 (encoded by PTPN11), an ubiquitously expressed PTP that transduces mitogenic, pro-survival, cell fate and/or pro-migratory signals from numerous growth factor-, cytokine- and extracellular matrix receptors. In malignancies, SHP2 is hyperactivated either downstream of oncoproteins or by mutations.We provide analysis of a primary triple-negative breast tumor grown as xenografts in the presence or absence of SHP2 for 30 days. A primary triple-negative breast tumor (BT8) was transduced with a doxycycline-inducible lentiviral vector expressing a CTRL miR or SHP2 miR1 or SHP2 miR2. Cells from each group were injected in immunodeficient mice and after tumor development, the knockdown of SHP2 was induced for 30 days in vivo. At day 30, tumors were dissected and RNA isolated for gene expression analysis.

2012-01-16 | E-GEOD-35118 | biostudies-arrayexpress

Shp2 signaling suppresses senescence in PyMT-induced mammary gland cancer in mice.

| S-EPMC4474526 | biostudies-literature

Gene expression profiling of mouse mammary tumorspheres, mammospheres, and mammospheres induced to differentiate

Project description:Tumorpsheres and mammospheres were used to propagate mouse breast tumor-initiating cells and their normal stem/progenitor counterparts, respectively. Mammospheres induced to differentiate were used to model the more differentiated cells of the mouse mammary gland. We used microarrays to find differentrially expressed genes between tumorspheres, mammospheres, and mammospheres induced to differentiate Primary cells were isolate from either mouse mammary glands (FVB/N) or mouse mammary tumors and placed in stem cell media (MMTV-Neu [N2O2]. Spheres were passaged every 7 days for 3-5 passages and harvested for RNA isolation

2012-01-30 | E-GEOD-32463 | biostudies-arrayexpress

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