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Mechanisms of Matrix-Induced Chemoresistance of Breast Cancer Cells—Deciphering Novel Potential Targets for a Cell Sensitization

Tumor cell binding to microenvironment components such as collagen type 1 (COL1) attenuates the sensitivity to cytotoxic drugs like cisplatin (CDDP) or mitoxantrone (MX), referred to as cell adhesion mediated drug resistance (CAM-DR). CAM-DR is considered as the onset for resistance mutations, but u...

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Autores principales: Jakubzig, Bastian, Baltes, Fabian, Henze, Svenja, Schlesinger, Martin, Bendas, Gerd
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315379/
https://www.ncbi.nlm.nih.gov/pubmed/30563275
http://dx.doi.org/10.3390/cancers10120495
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author Jakubzig, Bastian
Baltes, Fabian
Henze, Svenja
Schlesinger, Martin
Bendas, Gerd
author_facet Jakubzig, Bastian
Baltes, Fabian
Henze, Svenja
Schlesinger, Martin
Bendas, Gerd
author_sort Jakubzig, Bastian
collection PubMed
description Tumor cell binding to microenvironment components such as collagen type 1 (COL1) attenuates the sensitivity to cytotoxic drugs like cisplatin (CDDP) or mitoxantrone (MX), referred to as cell adhesion mediated drug resistance (CAM-DR). CAM-DR is considered as the onset for resistance mutations, but underlying mechanisms remain elusive. To evaluate CAM-DR as target for sensitization strategies, we analyzed signaling pathways in human estrogen-positive MCF-7 and triple-negative MDA-MB-231 breast cancer cells by western blot, proteome profiler array and TOP-flash assay in presence of COL1. β1-Integrins, known to bind COL1, appear as key for mediating COL1-related resistance in both cell lines that primarily follows FAK/PI3K/AKT pathway in MCF-7, and MAPK pathway in MDA-MB-231 cells. Notably, pCREB is highly elevated in both cell lines. Consequently, blocking these pathways sensitizes the cells evidently to CDDP and MX treatment. Wnt signaling is not relevant in this context. A β1-integrin knockdown of MCF-7 cells (MCF-7-β1-kd) reveals a signaling shift from FAK/PI3K/AKT to MAPK pathway, thus CREB emerges as a promising primary target for sensitization in MDA-MB-231, and secondary target in MCF-7 cells. Concluding, we provide evidence for importance of CAM-DR in breast cancer cells and identify intracellular signaling pathways as targets to sensitize cells for cytotoxicity treatment regimes.
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spelling pubmed-63153792019-01-09 Mechanisms of Matrix-Induced Chemoresistance of Breast Cancer Cells—Deciphering Novel Potential Targets for a Cell Sensitization Jakubzig, Bastian Baltes, Fabian Henze, Svenja Schlesinger, Martin Bendas, Gerd Cancers (Basel) Article Tumor cell binding to microenvironment components such as collagen type 1 (COL1) attenuates the sensitivity to cytotoxic drugs like cisplatin (CDDP) or mitoxantrone (MX), referred to as cell adhesion mediated drug resistance (CAM-DR). CAM-DR is considered as the onset for resistance mutations, but underlying mechanisms remain elusive. To evaluate CAM-DR as target for sensitization strategies, we analyzed signaling pathways in human estrogen-positive MCF-7 and triple-negative MDA-MB-231 breast cancer cells by western blot, proteome profiler array and TOP-flash assay in presence of COL1. β1-Integrins, known to bind COL1, appear as key for mediating COL1-related resistance in both cell lines that primarily follows FAK/PI3K/AKT pathway in MCF-7, and MAPK pathway in MDA-MB-231 cells. Notably, pCREB is highly elevated in both cell lines. Consequently, blocking these pathways sensitizes the cells evidently to CDDP and MX treatment. Wnt signaling is not relevant in this context. A β1-integrin knockdown of MCF-7 cells (MCF-7-β1-kd) reveals a signaling shift from FAK/PI3K/AKT to MAPK pathway, thus CREB emerges as a promising primary target for sensitization in MDA-MB-231, and secondary target in MCF-7 cells. Concluding, we provide evidence for importance of CAM-DR in breast cancer cells and identify intracellular signaling pathways as targets to sensitize cells for cytotoxicity treatment regimes. MDPI 2018-12-06 /pmc/articles/PMC6315379/ /pubmed/30563275 http://dx.doi.org/10.3390/cancers10120495 Text en © 2018 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
Jakubzig, Bastian
Baltes, Fabian
Henze, Svenja
Schlesinger, Martin
Bendas, Gerd
Mechanisms of Matrix-Induced Chemoresistance of Breast Cancer Cells—Deciphering Novel Potential Targets for a Cell Sensitization
title Mechanisms of Matrix-Induced Chemoresistance of Breast Cancer Cells—Deciphering Novel Potential Targets for a Cell Sensitization
title_full Mechanisms of Matrix-Induced Chemoresistance of Breast Cancer Cells—Deciphering Novel Potential Targets for a Cell Sensitization
title_fullStr Mechanisms of Matrix-Induced Chemoresistance of Breast Cancer Cells—Deciphering Novel Potential Targets for a Cell Sensitization
title_full_unstemmed Mechanisms of Matrix-Induced Chemoresistance of Breast Cancer Cells—Deciphering Novel Potential Targets for a Cell Sensitization
title_short Mechanisms of Matrix-Induced Chemoresistance of Breast Cancer Cells—Deciphering Novel Potential Targets for a Cell Sensitization
title_sort mechanisms of matrix-induced chemoresistance of breast cancer cells—deciphering novel potential targets for a cell sensitization
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315379/
https://www.ncbi.nlm.nih.gov/pubmed/30563275
http://dx.doi.org/10.3390/cancers10120495
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