miR-200c sensitizes breast cancer cells to doxorubicin treatment by decreasing TrkB and Bmi1 expression
Acquired resistance to classical chemotherapeutics is a major obstacle in cancer treatment. Doxorubicin is frequently used in breast cancer therapy either as single-agent or in combination with other drugs like docetaxel and cyclophosphamide. All these chemotherapies have in common that they are adm...
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| creator | Kopp, Florian Oak, Prajakta S Wagner, Ernst Roidl, Andreas |
| description | Acquired resistance to classical chemotherapeutics is a major obstacle in cancer treatment. Doxorubicin is frequently used in breast cancer therapy either as single-agent or in combination with other drugs like docetaxel and cyclophosphamide. All these chemotherapies have in common that they are administered sequentially and often result in chemoresistance. Here, we mimicked this pulse therapy of breast cancer patients in an in vitro cell culture model, where the epithelial breast cancer cell line BT474 was sequentially treated with doxorubicin for several treatment cycles. In consequence, we obtained chemoresistant cells displaying a mesenchymal-like phenotype with decreased levels of miR-200c. To investigate the involvement of miR-200c in resistance formation, we inhibited and overexpressed miR-200c in different cell lines. Thereby, the cells were rendered more resistant or susceptible to doxorubicin treatment. Moreover, the receptor tyrosine kinase TrkB and the transcriptional repressor Bmi1 were identified as miR-200c targets mediating the drug resistance. Hence, we provide a mechanism of acquired resistance to doxorubicin that is caused by the loss of miR-200c. Along with this, our study demonstrates the complex network of microRNA mediated chemoresistance highlighting the challenges in cancer therapy and the importance of novel microRNA-modulating anticancer agents. |
| doi_str_mv | 10.1371/journal.pone.0050469 |
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Doxorubicin is frequently used in breast cancer therapy either as single-agent or in combination with other drugs like docetaxel and cyclophosphamide. All these chemotherapies have in common that they are administered sequentially and often result in chemoresistance. Here, we mimicked this pulse therapy of breast cancer patients in an in vitro cell culture model, where the epithelial breast cancer cell line BT474 was sequentially treated with doxorubicin for several treatment cycles. In consequence, we obtained chemoresistant cells displaying a mesenchymal-like phenotype with decreased levels of miR-200c. To investigate the involvement of miR-200c in resistance formation, we inhibited and overexpressed miR-200c in different cell lines. Thereby, the cells were rendered more resistant or susceptible to doxorubicin treatment. Moreover, the receptor tyrosine kinase TrkB and the transcriptional repressor Bmi1 were identified as miR-200c targets mediating the drug resistance. Hence, we provide a mechanism of acquired resistance to doxorubicin that is caused by the loss of miR-200c. Along with this, our study demonstrates the complex network of microRNA mediated chemoresistance highlighting the challenges in cancer therapy and the importance of novel microRNA-modulating anticancer agents.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0050469</identifier><identifier>PMID: 23209748</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Analysis ; Anthracyclines ; Anticancer properties ; Antineoplastic Agents - pharmacology ; Antitumor agents ; Biology ; Biotechnology ; Breast cancer ; Breast Neoplasms - genetics ; Breast Neoplasms - metabolism ; Cancer ; Cancer therapies ; Cell culture ; Cell Line, Tumor ; Chemoresistance ; Chemotherapy ; Cyclophosphamide ; Cytotoxicity ; Doxorubicin ; Doxorubicin - pharmacology ; Drug resistance ; Drug therapy ; Drugs ; Evolution, Molecular ; Gene Expression Regulation, Neoplastic ; Health aspects ; Humans ; Immunoblotting ; Medicine ; Mesenchyme ; Metastasis ; MicroRNA ; MicroRNAs ; MicroRNAs - genetics ; MicroRNAs - metabolism ; miRNA ; Pharmaceuticals ; Pharmacy ; Polycomb Repressive Complex 1 - genetics ; Polycomb Repressive Complex 1 - metabolism ; Prostate ; Protein-tyrosine kinase receptors ; Receptor, trkB - genetics ; Receptor, trkB - metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Ribonucleic acid ; RNA ; Stem cells ; Target recognition ; Therapy ; Transcription ; TrkB receptors ; Tyrosine</subject><ispartof>PloS one, 2012-11, Vol.7 (11), p.e50469</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Kopp et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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Doxorubicin is frequently used in breast cancer therapy either as single-agent or in combination with other drugs like docetaxel and cyclophosphamide. All these chemotherapies have in common that they are administered sequentially and often result in chemoresistance. Here, we mimicked this pulse therapy of breast cancer patients in an in vitro cell culture model, where the epithelial breast cancer cell line BT474 was sequentially treated with doxorubicin for several treatment cycles. In consequence, we obtained chemoresistant cells displaying a mesenchymal-like phenotype with decreased levels of miR-200c. To investigate the involvement of miR-200c in resistance formation, we inhibited and overexpressed miR-200c in different cell lines. Thereby, the cells were rendered more resistant or susceptible to doxorubicin treatment. Moreover, the receptor tyrosine kinase TrkB and the transcriptional repressor Bmi1 were identified as miR-200c targets mediating the drug resistance. 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Doxorubicin is frequently used in breast cancer therapy either as single-agent or in combination with other drugs like docetaxel and cyclophosphamide. All these chemotherapies have in common that they are administered sequentially and often result in chemoresistance. Here, we mimicked this pulse therapy of breast cancer patients in an in vitro cell culture model, where the epithelial breast cancer cell line BT474 was sequentially treated with doxorubicin for several treatment cycles. In consequence, we obtained chemoresistant cells displaying a mesenchymal-like phenotype with decreased levels of miR-200c. To investigate the involvement of miR-200c in resistance formation, we inhibited and overexpressed miR-200c in different cell lines. Thereby, the cells were rendered more resistant or susceptible to doxorubicin treatment. Moreover, the receptor tyrosine kinase TrkB and the transcriptional repressor Bmi1 were identified as miR-200c targets mediating the drug resistance. Hence, we provide a mechanism of acquired resistance to doxorubicin that is caused by the loss of miR-200c. Along with this, our study demonstrates the complex network of microRNA mediated chemoresistance highlighting the challenges in cancer therapy and the importance of novel microRNA-modulating anticancer agents.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23209748</pmid><doi>10.1371/journal.pone.0050469</doi><tpages>e50469</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Analysis Anthracyclines Anticancer properties Antineoplastic Agents - pharmacology Antitumor agents Biology Biotechnology Breast cancer Breast Neoplasms - genetics Breast Neoplasms - metabolism Cancer Cancer therapies Cell culture Cell Line, Tumor Chemoresistance Chemotherapy Cyclophosphamide Cytotoxicity Doxorubicin Doxorubicin - pharmacology Drug resistance Drug therapy Drugs Evolution, Molecular Gene Expression Regulation, Neoplastic Health aspects Humans Immunoblotting Medicine Mesenchyme Metastasis MicroRNA MicroRNAs MicroRNAs - genetics MicroRNAs - metabolism miRNA Pharmaceuticals Pharmacy Polycomb Repressive Complex 1 - genetics Polycomb Repressive Complex 1 - metabolism Prostate Protein-tyrosine kinase receptors Receptor, trkB - genetics Receptor, trkB - metabolism Reverse Transcriptase Polymerase Chain Reaction Ribonucleic acid RNA Stem cells Target recognition Therapy Transcription TrkB receptors Tyrosine |
| title | miR-200c sensitizes breast cancer cells to doxorubicin treatment by decreasing TrkB and Bmi1 expression |
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