Cargando…
Kinetic Modeling of DUSP Regulation in Herceptin-Resistant HER2-Positive Breast Cancer
Background: HER2 (human epidermal growth factor 2)-positive breast cancer is an aggressive type of breast cancer characterized by the overexpression of the receptor-type protein tyrosine kinase HER2 or amplification of the HER2 gene. It is commonly treated by the drug trastuzumab (Herceptin), but re...
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723192/ https://www.ncbi.nlm.nih.gov/pubmed/31357550 http://dx.doi.org/10.3390/genes10080568 |
_version_ | 1783448712187478016 |
---|---|
author | Buiga, Petronela Elson, Ari Tabernero, Lydia Schwartz, Jean-Marc |
author_facet | Buiga, Petronela Elson, Ari Tabernero, Lydia Schwartz, Jean-Marc |
author_sort | Buiga, Petronela |
collection | PubMed |
description | Background: HER2 (human epidermal growth factor 2)-positive breast cancer is an aggressive type of breast cancer characterized by the overexpression of the receptor-type protein tyrosine kinase HER2 or amplification of the HER2 gene. It is commonly treated by the drug trastuzumab (Herceptin), but resistance to its action frequently develops and limits its therapeutic benefit. Dual-specificity phosphatases (DUSPs) were previously highlighted as central regulators of HER2 signaling; therefore, understanding their role is crucial to designing new strategies to improve the efficacy of Herceptin treatment. We investigated whether inhibiting certain DUSPs re-sensitized Herceptin-resistant breast cancer cells to the drug. We built a series of kinetic models incorporating the key players of HER2 signaling pathways and simulating a range of inhibition intensities. The simulation results were compared to live tumor cells in culture, and showed good agreement with the experimental analyses. In particular, we observed that Herceptin-resistant DUSP16-silenced breast cancer cells became more responsive to the drug when treated for 72 h with Herceptin, showing a decrease in resistance, in agreement with the model predictions. Overall, we showed that the kinetic modeling of signaling pathways is able to generate predictions that assist experimental research in the identification of potential targets for cancer treatment. |
format | Online Article Text |
id | pubmed-6723192 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-67231922019-09-10 Kinetic Modeling of DUSP Regulation in Herceptin-Resistant HER2-Positive Breast Cancer Buiga, Petronela Elson, Ari Tabernero, Lydia Schwartz, Jean-Marc Genes (Basel) Article Background: HER2 (human epidermal growth factor 2)-positive breast cancer is an aggressive type of breast cancer characterized by the overexpression of the receptor-type protein tyrosine kinase HER2 or amplification of the HER2 gene. It is commonly treated by the drug trastuzumab (Herceptin), but resistance to its action frequently develops and limits its therapeutic benefit. Dual-specificity phosphatases (DUSPs) were previously highlighted as central regulators of HER2 signaling; therefore, understanding their role is crucial to designing new strategies to improve the efficacy of Herceptin treatment. We investigated whether inhibiting certain DUSPs re-sensitized Herceptin-resistant breast cancer cells to the drug. We built a series of kinetic models incorporating the key players of HER2 signaling pathways and simulating a range of inhibition intensities. The simulation results were compared to live tumor cells in culture, and showed good agreement with the experimental analyses. In particular, we observed that Herceptin-resistant DUSP16-silenced breast cancer cells became more responsive to the drug when treated for 72 h with Herceptin, showing a decrease in resistance, in agreement with the model predictions. Overall, we showed that the kinetic modeling of signaling pathways is able to generate predictions that assist experimental research in the identification of potential targets for cancer treatment. MDPI 2019-07-26 /pmc/articles/PMC6723192/ /pubmed/31357550 http://dx.doi.org/10.3390/genes10080568 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Buiga, Petronela Elson, Ari Tabernero, Lydia Schwartz, Jean-Marc Kinetic Modeling of DUSP Regulation in Herceptin-Resistant HER2-Positive Breast Cancer |
title | Kinetic Modeling of DUSP Regulation in Herceptin-Resistant HER2-Positive Breast Cancer |
title_full | Kinetic Modeling of DUSP Regulation in Herceptin-Resistant HER2-Positive Breast Cancer |
title_fullStr | Kinetic Modeling of DUSP Regulation in Herceptin-Resistant HER2-Positive Breast Cancer |
title_full_unstemmed | Kinetic Modeling of DUSP Regulation in Herceptin-Resistant HER2-Positive Breast Cancer |
title_short | Kinetic Modeling of DUSP Regulation in Herceptin-Resistant HER2-Positive Breast Cancer |
title_sort | kinetic modeling of dusp regulation in herceptin-resistant her2-positive breast cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723192/ https://www.ncbi.nlm.nih.gov/pubmed/31357550 http://dx.doi.org/10.3390/genes10080568 |
work_keys_str_mv | AT buigapetronela kineticmodelingofduspregulationinherceptinresistanther2positivebreastcancer AT elsonari kineticmodelingofduspregulationinherceptinresistanther2positivebreastcancer AT tabernerolydia kineticmodelingofduspregulationinherceptinresistanther2positivebreastcancer AT schwartzjeanmarc kineticmodelingofduspregulationinherceptinresistanther2positivebreastcancer |