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

Background25% of breast cancer patients suffer from aggressive HER2-positive tumours that are characterised by overexpression of the HER2 protein or by its increased tyrosine kinase activity. Herceptin is a major drug used to treat HER2 positive breast cancer. Understanding the molecular events that occur when breast cancer cells are exposed to Herceptin is therefore of significant importance. Dual specificity phosphatases (DUSPs) are central regulators of cell signalling that function downstream of HER2, but their role in the cellular response to Herceptin is mostly unknown. This study aims to model the initial effects of Herceptin exposure on DUSPs in HER2-positive breast cancer cells using Boolean modelling.ResultsWe experimentally measured expression time courses of 21 different DUSPs between 0 and 24 h following Herceptin treatment of human MDA-MB-453 HER2-positive breast cancer cells. We clustered these time courses into patterns of similar dynamics over time. In parallel, we built a series of Boolean models representing the known regulatory mechanisms of DUSPs and then demonstrated that the dynamics predicted by the models is in agreement with the experimental data. Furthermore, we used the models to predict regulatory mechanisms of DUSPs, where these mechanisms were partially known.ConclusionsBoolean modelling is a powerful technique to investigate and understand signalling pathways. We obtained an understanding of different regulatory pathways in breast cancer and new insights on how these signalling pathways are activated. This method can be generalized to other drugs and longer time courses to better understand how resistance to drugs develops in cancer cells over time.

[1]  H. Kitano,et al.  A comprehensive pathway map of epidermal growth factor receptor signaling , 2005, Molecular systems biology.

[2]  Kelly K. Haagenson,et al.  The role of MAP kinases and MAP kinase phosphatase-1 in resistance to breast cancer treatment , 2010, Cancer and Metastasis Reviews.

[3]  D. Lauffenburger,et al.  Input–output behavior of ErbB signaling pathways as revealed by a mass action model trained against dynamic data , 2009, Molecular systems biology.

[4]  Joanna M. Sasin,et al.  Protein Tyrosine Phosphatases in the Human Genome , 2004, Cell.

[5]  J. Budczies,et al.  DUSP4 is associated with increased resistance against anti-HER2 therapy in breast cancer , 2017, Oncotarget.

[6]  Hsien-yu Wang,et al.  Overexpression of mitogen-activated protein kinase phosphatases MKP1, MKP2 in human breast cancer. , 2003, Cancer letters.

[7]  M. Duffy,et al.  Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer , 2013, Oncotarget.

[8]  Xiaoping Yu,et al.  Anthocyanins inhibit trastuzumab-resistant breast cancer in vitro and in vivo. , 2016, Molecular medicine reports.

[9]  Jean-Marc Schwartz,et al.  A MAPK-Driven Feedback Loop Suppresses Rac Activity to Promote RhoA-Driven Cancer Cell Invasion , 2016, PLoS Comput. Biol..

[10]  John D. Hunter,et al.  Matplotlib: A 2D Graphics Environment , 2007, Computing in Science & Engineering.

[11]  R. Nahta,et al.  Targeting Bcl-2 in Herceptin-Resistant Breast Cancer Cell Lines. , 2011, Current pharmacogenomics and personalized medicine.

[12]  Song Li,et al.  Boolean network simulations for life scientists , 2008, Source Code for Biology and Medicine.

[13]  R. Finn,et al.  Current approaches and future directions in the treatment of HER2-positive breast cancer. , 2013, Cancer treatment reviews.

[14]  C. Ji,et al.  Molecular cloning and characterization of a novel dual-specificity phosphatase 23 gene from human fetal brain. , 2004, The international journal of biochemistry & cell biology.

[15]  W Godolphin,et al.  Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. , 1989, Science.

[16]  E. Nishida,et al.  Regulation of MAP kinases by MAP kinase phosphatases. , 2007, Biochimica et biophysica acta.

[17]  M. Ahram,et al.  Alteration of gene expression in MDA-MB-453 breast cancer cell line in response to continuous exposure to Trastuzumab. , 2016, Gene.

[18]  S. Keyse,et al.  The regulation of oncogenic Ras/ERK signalling by dual-specificity mitogen activated protein kinase phosphatases (MKPs) , 2016, Seminars in cell & developmental biology.

[19]  Tim Beißbarth,et al.  Boolean ErbB network reconstructions and perturbation simulations reveal individual drug response in different breast cancer cell lines , 2014, BMC Systems Biology.

[20]  H. Gautrey,et al.  The HER2 Signaling Network in Breast Cancer—Like a Spider in its Web , 2014, Journal of Mammary Gland Biology and Neoplasia.

[21]  J. Woo,et al.  Induction of caspase-dependent apoptosis by apigenin by inhibiting STAT3 signaling in HER2-overexpressing MDA-MB-453 breast cancer cells. , 2014, Anticancer research.

[22]  Rui-Sheng Wang,et al.  Boolean modeling in systems biology: an overview of methodology and applications , 2012, Physical biology.

[23]  M. Loda,et al.  Expression of mitogen-activated protein kinase phosphatase-1 in the early phases of human epithelial carcinogenesis. , 1996, The American journal of pathology.

[24]  F. Claret,et al.  Trastuzumab: Updated Mechanisms of Action and Resistance in Breast Cancer , 2012, Front. Oncol..

[25]  Steffen Klamt,et al.  The Logic of EGFR/ErbB Signaling: Theoretical Properties and Analysis of High-Throughput Data , 2009, PLoS Comput. Biol..

[26]  Jenny C. Chang,et al.  Trastuzumab-resistant cells rely on a HER2-PI3K-FoxO-survivin axis and are sensitive to PI3K inhibitors. , 2013, Cancer research.

[27]  T. Shen,et al.  HER2-specific T lymphocytes kill both trastuzumab-resistant and trastuzumab-sensitive breast cell lines in vitro , 2012, Chinese journal of cancer research = Chung-kuo yen cheng yen chiu.

[28]  Fan Zhang,et al.  Computational cell fate modelling for discovery of rewiring in apoptotic network for enhanced cancer drug sensitivity , 2015, BMC Systems Biology.

[29]  Naoto T. Ueno,et al.  P27kip1 Down-Regulation Is Associated with Trastuzumab Resistance in Breast Cancer Cells , 2004, Cancer Research.

[30]  P. Lazo.  Emerging signaling pathways in tumor biology , 2010 .

[31]  Maido Remm,et al.  Enhancements and modifications of primer design program Primer3 , 2007, Bioinform..

[32]  S. Hilsenbeck,et al.  Different mechanisms for resistance to trastuzumab versus lapatinib in HER2- positive breast cancers -- role of estrogen receptor and HER2 reactivation , 2011, Breast Cancer Research.

[33]  J. Schwartz,et al.  Dynamics of DNA Damage Induced Pathways to Cancer , 2012, PloS one.

[34]  T. Mustelin,et al.  Inhibitory Role for Dual Specificity Phosphatase VHR in T Cell Antigen Receptor and CD28-induced Erk and Jnk Activation* , 2001, The Journal of Biological Chemistry.

[35]  Luiz Eduardo Soares de Oliveira,et al.  A Dataset for Breast Cancer Histopathological Image Classification , 2016, IEEE Transactions on Biomedical Engineering.

[36]  B. Faircloth,et al.  Primer3—new capabilities and interfaces , 2012, Nucleic acids research.

[37]  Denis Thieffry,et al.  Integrative Modelling of the Influence of MAPK Network on Cancer Cell Fate Decision , 2013, PLoS Comput. Biol..

[38]  M. Arbushites,et al.  Single-agent lapatinib for HER2-overexpressing advanced or metastatic breast cancer that progressed on first- or second-line trastuzumab-containing regimens. , 2009, Annals of oncology : official journal of the European Society for Medical Oncology.

[39]  M. L. Martins,et al.  Boolean Network Model for Cancer Pathways: Predicting Carcinogenesis and Targeted Therapy Outcomes , 2013, PloS one.

[40]  Laurence Calzone,et al.  Correction: Integrative Modelling of the Influence of MAPK Network on Cancer Cell Fate Decision , 2013, PLoS Computational Biology.

[41]  F. Bertucci,et al.  ERBB2 phosphorylation and trastuzumab sensitivity of breast cancer cell lines , 2007, Oncogene.

[42]  Xuelin Huang,et al.  An improvement of the 2ˆ(-delta delta CT) method for quantitative real-time polymerase chain reaction data analysis. , 2013, Biostatistics, bioinformatics and biomathematics.

[43]  Holger Fröhlich,et al.  Modeling ERBB receptor-regulated G1/S transition to find novel targets for de novo trastuzumab resistance , 2009, BMC Systems Biology.

[44]  Pedro J. Ballester,et al.  Biochemical evaluation of virtual screening methods reveals a cell-active inhibitor of the cancer-promoting phosphatases of regenerating liver , 2014, European journal of medicinal chemistry.

[45]  Chang Gong,et al.  Up-regulation of miR-21 Mediates Resistance to Trastuzumab Therapy for Breast Cancer* , 2011, The Journal of Biological Chemistry.

[46]  K. Takagaki,et al.  Characterization of a novel low-molecular-mass dual-specificity phosphatase-3 (LDP-3) that enhances activation of JNK and p38. , 2004, The Biochemical journal.

[47]  J. Denu,et al.  Structural basis for the recognition of a bisphosphorylated MAP kinase peptide by human VHR protein Phosphatase. , 2002, Biochemistry.

[48]  J. Woodgett,et al.  The stress activated protein kinase pathway. , 1996, Cancer surveys.

[49]  S. Keyse,et al.  Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases , 2007, Oncogene.

[50]  J. Rüschoff,et al.  HER2/ErbB2 activates HSF1 and thereby controls HSP90 clients including MIF in HER2-overexpressing breast cancer , 2014, Cell Death and Disease.