Research article Special Issues

Mathematical modelling of Her2 (ErbB2) PI3K/AKT signalling pathways during breast carcinogenesis to include PTPD2

  • Received: 07 April 2020 Accepted: 27 May 2020 Published: 04 June 2020
  • MSC : 97M60

  • ErbB2 overexpression plays an important pathogenic role in breast cancer and acts via phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signalling pathways. Mathematical models for the PI3K/AKT signalling pathways have been derived but have not incorporated a newly defined positive regulator of the ErbB2 signalling network, phosphatidic acid-protein-tyrosine phosphatase D2 (PTPD2). We hypothesize that PTPD2 acts on the AKT signalling pathway by binding PA to PTPD2 and participates in AKT phosphorylation through PIP3. Based on this, a new mathematical model of ErbB2/P13K/AKT and PLD2/PTPD2 pathways was derived using 22 ordinary differential equations. The derived simulation results were consistent with the experimental results. This model is used to study the change of ppAKT concentration with time at different initial concentrations of PDPD2, PLD2, PI3K and PTEN in the signal pathway. Taken together, these observations suggest therapeutic approaches for erbb2-positive breast cancer which is resistant to ErbB2 targeted therapy based on inhibitors for PI3K, PTPD2 or PLD2.

    Citation: Bing Ji, Jiawei Bai, Luis A J Mur, Mengjia Zou, Jiwan Han, Rui Gao, Qing Yang. Mathematical modelling of Her2 (ErbB2) PI3K/AKT signalling pathways during breast carcinogenesis to include PTPD2[J]. AIMS Mathematics, 2020, 5(5): 4946-4958. doi: 10.3934/math.2020316

    Related Papers:

  • ErbB2 overexpression plays an important pathogenic role in breast cancer and acts via phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signalling pathways. Mathematical models for the PI3K/AKT signalling pathways have been derived but have not incorporated a newly defined positive regulator of the ErbB2 signalling network, phosphatidic acid-protein-tyrosine phosphatase D2 (PTPD2). We hypothesize that PTPD2 acts on the AKT signalling pathway by binding PA to PTPD2 and participates in AKT phosphorylation through PIP3. Based on this, a new mathematical model of ErbB2/P13K/AKT and PLD2/PTPD2 pathways was derived using 22 ordinary differential equations. The derived simulation results were consistent with the experimental results. This model is used to study the change of ppAKT concentration with time at different initial concentrations of PDPD2, PLD2, PI3K and PTEN in the signal pathway. Taken together, these observations suggest therapeutic approaches for erbb2-positive breast cancer which is resistant to ErbB2 targeted therapy based on inhibitors for PI3K, PTPD2 or PLD2.


    加载中


    [1] K. Polyak, Heterogeneity in breast cancer, J. Clin. Invest., 121 (2011), 3786-3788. doi: 10.1172/JCI60534
    [2] E. M. Bublil, Y. Yarden, The EGF receptor family: spearheading a merger of signaling and therapeutics, Curr. Opin. Cell Biol., 19 (2007), 124-134. doi: 10.1016/j.ceb.2007.02.008
    [3] D. J. Slamon, G. M. Clark, S. G. Wonf, et al. HUMAN-BREAST CANCER - CORRELATION OF RELAPSE AND SURVIVAL WITH AMPLIFICATION OF THE HER-2 NEU ONCOGENE, Science, 235 (1987), 177-182. doi: 10.1126/science.3798106
    [4] D. H. Yu, M. C. Hung, Overexpression of ErbB2 in cancer and ErbB2-targeting strategies, Oncogene, 19 (2000), 6115-6121. doi: 10.1038/sj.onc.1203972
    [5] W. Tai, R. Mahato, K. Cheng, The role of HER2 in cancer therapy and targeted drug delivery, J. Control RELEASE, 146 (2010), 264-275. doi: 10.1016/j.jconrel.2010.04.009
    [6] F. Xu, L. Na, Y. Li, et al. Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours, CELL Biosci., 10 (2020), 1-12. doi: 10.1186/s13578-019-0370-3
    [7] B. Ji, Y. Zhang, C. Zhen, et al. Mathematical modelling of bone remodelling cycles including the NF kappa B signalling pathway, Comput. Biol. Med., 107 (2019), 257-264. doi: 10.1016/j.compbiomed.2019.03.003
    [8] B. Ji, J. Chen, C. Zhen, et al. Mathematical modelling of the role of Endo180 network in the development of metastatic bone disease in prostate cancer, Comput. Biol. Med., 117 (2020), 103619.
    [9] B. Schoeberl, C. Eichler-Jonsson, E. D. Gilles, et al. Computational modeling of the dynamics of the MAP kinase cascade activated by surface and internalized EGF receptors, Nat. Biotechnol., 20 (2002), 370-375. doi: 10.1038/nbt0402-370
    [10] M. Hatakeyama, S. Kimura, T. Naka, et al. (2003) A computational model on the modulation of mitogen-activated protein kinase (MAPK) and Akt pathways in heregulin-induced ErbB signalling, Biochem. J., 373 (2003), 451-463.
    [11] G. Koh, H. F. C. Teong, M. V. Clément, et al. A decompositional approach to parameter estimation in pathway modeling: A case study of the Akt and MAPK pathways and their crosstalk, Bioinformatics, 22 (2006), e271-e280.
    [12] S. Itani, J. Gray, C. J. Tomlin, An ODE model for the HER2/3-AKT signaling pathway in cancers that overexpress HER2, Proc. 2010 Am. Control Conf., (2010), 1235-1241.
    [13] D. C. Kirouac, J. Y. Du, J. Lahdenranta, et al. Computational Modeling of ERBB2-Amplified Breast Cancer Identifies Combined ErbB2/3 Blockade as Superior to the Combination of MEK and AKT Inhibitors, Sci. Signal., 6 (2013), ra68.
    [14] E. Shankar, M. C. Weis, J. Avva, et al. Complex Systems Biology Approach in Connecting PI3K-Akt and NF-kappa B Pathways in Prostate Cancer, CELLS, 8 (2019).
    [15] Z. Eroglu, T. Tagawa, G. Somlo, Human Epidermal Growth Factor Receptor Family-Targeted Therapies in the Treatment of HER2-Overexpressing Breast Cancer, Oncologist, 19 (2014), 135-150. doi: 10.1634/theoncologist.2013-0283
    [16] M. Ramesh, N. Krishnan, S. K. Muthuswamy, et al. A novel phosphatidic acid-protein-tyrosine phosphatase D2 axis is essential for ERBB2 signaling in mammary epithelial cells, J. Biol. Chem., 290 (2015), 9646-9659. doi: 10.1074/jbc.M114.627968
    [17] F. J. Esteva, H. Guo, S. Zhang, et al. PTEN, PIK3CA, p-AKT, and p-p70S6K Status Association with Trastuzumab Response and Survival in Patients with HER2-Positive Metastatic Breast Cancer, Am. J. Pathol., 177 (2010), 1647-1656. doi: 10.2353/ajpath.2010.090885
    [18] R. Slaaby, T. Jensen, H. S. Hansen, et al. PLD2 complexes with the EGF receptor and undergoes tyrosine phosphorylation at a single site upon agonist stimulation, J. Biol. Chem., 273 (1998), 33722-33727. doi: 10.1074/jbc.273.50.33722
    [19] R. C. Bruntz, C. W. Lindsley, H. A. Brown, Phospholipase D Signaling Pathways and Phosphatidic Acid as Therapeutic Targets in Cancer, Pharmacol. Rev., 66 (2014), 1033-1079. doi: 10.1124/pr.114.009217
    [20] Y. Yarden, M. X. Sliwkowski, Untangling the ErbB signalling network, Nat. Rev. Mol. CELL Biol., 2 (2001), 127-137. doi: 10.1038/35052073
    [21] J. Saez-Rodriguez, A. MacNamara, S. Cook, Modeling Signaling Networks to Advance New Cancer Therapies, ANNU. REV. BIOMED. ENG., 17 (2015), 143-163. doi: 10.1146/annurev-bioeng-071813-104927
    [22] A. Eladdadi, D. Isaacson, A mathematical model for the effects of HER2 overexpression on cell proliferation in breast cancer, Bull. Math. Biol., 70 (2008), 1707-1729. doi: 10.1007/s11538-008-9315-4
    [23] C. Frank, H. Keilhack, F. Opitz, et al. Binding of phosphatidic acid to the protein-tyrosine phosphatase SHP-1 as a basis for activity modulation, Biochemistry, 38 (1999), 11993-12002. doi: 10.1021/bi982586w
    [24] P. E. Selvy, R. R. Lavieri, C. W. Lindsley, et al. Phospholipase D: Enzymology, Functionality, and Chemical Modulation, Chem. Rev., 111 (2011), 6064-6119. doi: 10.1021/cr200296t
    [25] Y. A. Adi, F. A. Kusumo, L. Aryati, et al. A Mathematical Model of Phosphorylation AKT in Acute Myeloid Leukemia, SYMPOSIUM ON BIOMATHEMATICS (SYMOMATH 2015), 1723 (2016), 030001.
    [26] L. Lenoci, M. Duvernay, S. Satchell, et al. Mathematical model of PAR1-mediated activation of human platelets, Mol. Biosyst., 7 (2011), 1129-1137. doi: 10.1039/c0mb00250j
    [27] R. J. Buxeda, J. T. Nickels, C. J. Belunis, et al. PHOSPHATIDYLINOSITOL 4-KINASE FROM SACCHAROMYCES-CEREVISIAE. KINETIC-ANALYSIS USING TRITON X-100 PHOSPHATIDYLINOSITOL-MIXED MICELLES, J. Biol. Chem., 266 (1991), 13859-13865.
    [28] L. G. Henage, J. H. Exton, H. A. Brown, Kinetic analysis of a mammalian phospholipase D - Allosteric modulation by monomeric GTPases, protein kinase C, and polyphosphoinositides, J. Biol. Chem., 281 (2006), 3408-3417. doi: 10.1074/jbc.M508800200
    [29] W. H. Tan, A. S. Popel, F. Mac Gabhann, Computational Model of Gab1/2-Dependent VEGFR2 Pathway to Akt Activation, PLoS One, 8 (2013), 1-17.
    [30] A. De Luca, M. R. Maiello, A. D'Alessio, et al. The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: role in cancer pathogenesis and implications for therapeutic approaches, Expert Opin. Ther. Tar., 16 (2012), S17-S27.
    [31] M. Kanehisa, S. Goto, Y. Sato, et al. KEGG for integration and interpretation of large-scale molecular data sets, Nucleic Acids Res., 40 (2012), D109-D114.
    [32] A. Dittrich, H. Gautrey, D. Browell, et al. The HER2 Signaling Network in Breast Cancer-Like a Spider in its Web, J. Mammary Gland Biol. Neoplasia, 19 (2014), 253-270. doi: 10.1007/s10911-014-9329-5
  • Reader Comments
  • © 2020 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)
通讯作者: 陈斌, bchen63@163.com
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索

Metrics

Article views(5001) PDF downloads(369) Cited by(2)

Article outline

Figures and Tables

Figures(7)  /  Tables(3)

/

DownLoad:  Full-Size Img  PowerPoint
Return
Return

Catalog