scholarly journals Regulation of dual specificity phosphatases in breast cancer during initial treatment with Herceptin: a Boolean model analysis

2018 ◽  
Vol 12 (S1) ◽  
Author(s):  
Petronela Buiga ◽  
Ari Elson ◽  
Lydia Tabernero ◽  
Jean-Marc Schwartz
Keyword(s):  
Breast Cancer ◽  
Initial Treatment ◽  
Model Analysis ◽  
Boolean Model ◽  
Dual Specificity ◽  
Dual Specificity Phosphatases

scholarly journals CDC25B partners with PP2A to induce AMPK activation and tumor suppression in triple negative breast cancer

NAR Cancer ◽  
2020 ◽  
Vol 2 (4) ◽  
Author(s):  
Junmei Cairns ◽  
Reynold C Ly ◽  
Nifang Niu ◽  
Krishna R Kalari ◽  
Erin E Carlson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Xenograft Model ◽  
Direct Interaction ◽  
Ampk Activation ◽  
Dual Specificity ◽  
Phosphatase 2A ◽  
Dual Specificity Phosphatases ◽  
Amp Activated Protein Kinase ◽  
Protein Kinase Signaling

Abstract Cell division cycle 25 (CDC25) dual specificity phosphatases positively regulate the cell cycle by activating cyclin-dependent kinase/cyclin complexes. Here, we demonstrate that in addition to its role in cell cycle regulation, CDC25B functions as a regulator of protein phosphatase 2A (PP2A), a major cellular Ser/Thr phosphatase, through its direct interaction with PP2A catalytic subunit. Importantly, CDC25B alters the regulation of AMP-activated protein kinase signaling (AMPK) by PP2A, increasing AMPK activity by inhibiting PP2A to dephosphorylate AMPK. CDC25B depletion leads to metformin resistance by inhibiting metformin-induced AMPK activation. Furthermore, dual inhibition of CDC25B and PP2A further inhibits growth of 3D organoids isolated from patient derived xenograft model of breast cancer compared to CDC25B inhibition alone. Our study identifies CDC25B as a regulator of PP2A, and uncovers a mechanism of controlling the activity of a key energy metabolism marker, AMPK.

scholarly journals Expression Profile of Tyrosine Phosphatases in HER2 Breast Cancer Cells and Tumors

2010 ◽  
Vol 32 (5-6) ◽  
pp. 361-372
Author(s):  
Maria Antonietta Lucci ◽  
Rosaria Orlandi ◽  
Tiziana Triulzi ◽  
Elda Tagliabue ◽  
Andrea Balsari ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Differentially Expressed ◽  
Her2 Overexpression ◽  
Her2 Positive ◽  
Signalling Molecules ◽  
Her2 Breast Cancer ◽  
Dual Specificity ◽  
Dual Specificity Phosphatases ◽  
Therapy Target ◽  
In Cells

Background: HER2-overexpression promotes malignancy by modulating signalling molecules, which include PTPs/DSPs (protein tyrosine and dual-specificity phosphatases). Our aim was to identify PTPs/DSPs displaying HER2-associated expression alterations.Methods: HER2 activity was modulated in MDA-MB-453 cells and PTPs/DSPs expression was analysed with a DNA oligoarray, by RT-PCR and immunoblotting. Two public breast tumor datasets were analysed to identify PTPs/DSPs differentially expressed in HER2-positive tumors.Results: In cells (1) HER2-inhibition up-regulated 4 PTPs (PTPRA, PTPRK, PTPN11, PTPN18) and 11 DSPs (7 MKPs [MAP Kinase Phosphatases], 2 PTP4, 2 MTMRs [Myotubularin related phosphatases]) and down-regulated 7 DSPs (2 MKPs, 2 MTMRs, CDKN3, PTEN, CDC25C); (2) HER2-activation with EGF affected 10 DSPs (5 MKPs, 2 MTMRs, PTP4A1, CDKN3, CDC25B) and PTPN13; 8 DSPs were found in both groups. Furthermore, 7 PTPs/DSPs displayed also altered protein level. Analysis of 2 breast cancer datasets identified 6 differentially expressed DSPs: DUSP6, strongly up-regulated in both datasets; DUSP10 and CDC25B, up-regulated; PTP4A2, CDC14A and MTMR11 down-regulated in one dataset.Conclusions: Several DSPs, mainly MKPs and, unexpectedly, MTMRs, were altered following HER2-modulation in cells and 3 DSPs (DUSP6, CDC25B and MTMR11) were altered in both cells and tumors. Among these, DUSP6, strongly up-regulated in HER2-positive tumors, would deserve further investigation as tumor marker or potential therapy target.

scholarly journals Modelling the role of dual specificity phosphatases in Herceptin resistant breast cancer cell lines

2019 ◽  
Author(s):  
Petronela Buiga ◽  
Ari Elson ◽  
Lydia Tabernero ◽  
Jean-Marc Schwartz
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Significant Proportion ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Boolean Models ◽  
Dual Specificity ◽  
Dual Specificity Phosphatases

AbstractBackgroundBreast cancer remains the most lethal type of cancer for women. A significant proportion of breast cancer cases are characterised by overexpression of the human epidermal growth factor receptor 2 protein (HER2). These cancers are commonly treated by Herceptin (Trastuzumab), but resistance to drug treatment frequently develops in tumour cells. Dual-specificity phosphatases (DUSPs) are thought to play a role in the mechanism of resistance, since some of them were reported to be overexpressed in tumours resistant to Herceptin.ResultsWe used a systems biology approach to investigate how DUSP overexpression could favour cell proliferation and to predict how this mechanism could be reversed by targeted inhibition of selected DUSPs. We measured the expression of 20 DUSP genes in two breast cancer cell lines following long-term (6 months) exposure to Herceptin, after confirming that these cells had become resistant to the drug. We constructed several Boolean models including specific substrates of each DUSP, and showed that our models correctly account for resistance when overexpressed DUSPs were kept activated. We then simulated inhibition of both individual and combinations of DUSPs, and determined conditions under which the resistance could be reversed.ConclusionsThese results show how a combination of experimental analysis and modelling help to understand cell survival mechanisms in breast cancer tumours, and crucially enable us to generate testable predictions potentially leading to new treatments of resistant tumours.

scholarly journals Structure of human dual-specificity phosphatase 7, a potential cancer drug target

2015 ◽  
Vol 71 (6) ◽  
pp. 650-656 ◽  
Author(s):  
George T. Lountos ◽  
Brian P. Austin ◽  
Joseph E. Tropea ◽  
David S. Waugh
Keyword(s):  
Catalytic Domain ◽  
Three Dimensional ◽  
Mitogen Activated Protein Kinase ◽  
Cancer Drug ◽  
Dual Specificity Phosphatase ◽  
Dual Specificity ◽  
Starting Point ◽  
Mitogen Activated Protein ◽  
Dual Specificity Phosphatases

Human dual-specificity phosphatase 7 (DUSP7/Pyst2) is a 320-residue protein that belongs to the mitogen-activated protein kinase phosphatase (MKP) subfamily of dual-specificity phosphatases. Although its precise biological function is still not fully understood, previous reports have demonstrated that DUSP7 is overexpressed in myeloid leukemia and other malignancies. Therefore, there is interest in developing DUSP7 inhibitors as potential therapeutic agents, especially for cancer. Here, the purification, crystallization and structure determination of the catalytic domain of DUSP7 (Ser141–Ser289/C232S) at 1.67 Å resolution are reported. The structure described here provides a starting point for structure-assisted inhibitor-design efforts and adds to the growing knowledge base of three-dimensional structures of the dual-specificity phosphatase family.

scholarly journals Dual-specificity phosphatases in mental and neurological disorders

2020 ◽  
pp. 101906
Author(s):  
Ning An ◽  
Katherine Bassil ◽  
Ghazi I. Al Jowf ◽  
Harry W.M. Steinbusch ◽  
Markus Rothermel ◽  
...  
Keyword(s):  
Neurological Disorders ◽  
Dual Specificity ◽  
Dual Specificity Phosphatases

scholarly journals Nuclear-Biased DUSP6 Expression is Associated with Cancer Spreading Including Brain Metastasis in Triple-Negative Breast Cancer

2019 ◽  
Vol 20 (12) ◽  
pp. 3080 ◽  
Author(s):  
Fan Wu ◽  
Robert D. McCuaig ◽  
Christopher R. Sutton ◽  
Abel H. Y. Tan ◽  
Yoshni Jeelall ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Cancer Progression ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Lung Metastases ◽  
Her2 Positive ◽  
Pathway Gene ◽  
Dual Specificity ◽  
The Brain

DUSP6 is a dual-specificity phosphatase (DUSP) involved in breast cancer progression, recurrence, and metastasis. DUSP6 is predominantly cytoplasmic in HER2+ primary breast cancer cells, but the expression and subcellular localization of DUSPs, especially DUSP6, in HER2-positive circulating tumor cells (CTCs) is unknown. Here we used the DEPArray system to identify and isolate CTCs from metastatic triple negative breast cancer (TNBC) patients and performed single-cell NanoString analysis to quantify cancer pathway gene expression in HER2-positive and HER2-negative CTC populations. All TNBC patients contained HER2-positive CTCs. HER2-positive CTCs were associated with increased ERK1/ERK2 expression, which are direct DUSP6 targets. DUSP6 protein expression was predominantly nuclear in breast CTCs and the brain metastases but not pleura or lung metastases of TNBC patients. Therefore, nuclear DUSP6 may play a role in the association with cancer spreading in TNBC patients, including brain metastasis.

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