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The sialyl-glycolipid stage-specific embryonic antigen 4 marks a subpopulation of chemotherapy-resistant breast cancer cells with mesenchymal features

INTRODUCTION: Chemotherapy resistance resulting in incomplete pathologic response is associated with high risk of metastasis and early relapse in breast cancer. The aim of this study was to identify and evaluate biomarkers of treatment-resistant tumor cells. METHODS: We performed a cell surface mark...

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Autores principales: Aloia, Andrea, Petrova, Evgeniya, Tomiuk, Stefan, Bissels, Ute, Déas, Olivier, Saini, Massimo, Zickgraf, Franziska Maria, Wagner, Steve, Spaich, Saskia, Sütterlin, Marc, Schneeweiss, Andreas, Reitberger, Manuel, Rüberg, Silvia, Gerstmayer, Bernhard, Agorku, David, Knöbel, Sebastian, Terranegra, Annalisa, Falleni, Monica, Soldati, Laura, Sprick, Martin Ronald, Trumpp, Andreas, Judde, Jean-Gabriel, Bosio, Andreas, Cairo, Stefano, Hardt, Olaf
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4660783/
https://www.ncbi.nlm.nih.gov/pubmed/26607327
http://dx.doi.org/10.1186/s13058-015-0652-6
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author Aloia, Andrea
Petrova, Evgeniya
Tomiuk, Stefan
Bissels, Ute
Déas, Olivier
Saini, Massimo
Zickgraf, Franziska Maria
Wagner, Steve
Spaich, Saskia
Sütterlin, Marc
Schneeweiss, Andreas
Reitberger, Manuel
Rüberg, Silvia
Gerstmayer, Bernhard
Agorku, David
Knöbel, Sebastian
Terranegra, Annalisa
Falleni, Monica
Soldati, Laura
Sprick, Martin Ronald
Trumpp, Andreas
Judde, Jean-Gabriel
Bosio, Andreas
Cairo, Stefano
Hardt, Olaf
author_facet Aloia, Andrea
Petrova, Evgeniya
Tomiuk, Stefan
Bissels, Ute
Déas, Olivier
Saini, Massimo
Zickgraf, Franziska Maria
Wagner, Steve
Spaich, Saskia
Sütterlin, Marc
Schneeweiss, Andreas
Reitberger, Manuel
Rüberg, Silvia
Gerstmayer, Bernhard
Agorku, David
Knöbel, Sebastian
Terranegra, Annalisa
Falleni, Monica
Soldati, Laura
Sprick, Martin Ronald
Trumpp, Andreas
Judde, Jean-Gabriel
Bosio, Andreas
Cairo, Stefano
Hardt, Olaf
author_sort Aloia, Andrea
collection PubMed
description INTRODUCTION: Chemotherapy resistance resulting in incomplete pathologic response is associated with high risk of metastasis and early relapse in breast cancer. The aim of this study was to identify and evaluate biomarkers of treatment-resistant tumor cells. METHODS: We performed a cell surface marker screen in triple-negative breast cancer patient-derived xenograft models treated with standard care genotoxic chemotherapy. Global expression profiling was used to further characterize the identified treatment-resistant subpopulations. RESULTS: High expression of sialyl-glycolipid stage-specific embryonic antigen 4 (SSEA4) was found in residual tumor cells surviving chemotherapy and in samples from metastatic patients who relapsed after neoadjuvant chemotherapy. Gene and microRNA (miRNA) expression profiling linked SSEA4 positivity with a mesenchymal phenotype and a deregulation of drug resistance pathways. Functional assays demonstrated a direct link between epithelial–mesenchymal transition (EMT) and SSEA4 expression. Interestingly, SSEA4 expression, EMT, and drug resistance seemed to be regulated posttranscriptionally. Finally, high expression of CMP-N-acetylneuraminate-β-galactosamide-α-2,3-sialyltransferase 2 (ST3GAL2), the rate-limiting enzyme of SSEA4 synthesis, was found to be associated with poor clinical outcome in breast and ovarian cancer patients treated with chemotherapy. CONCLUSIONS: In this study, we identified SSEA4 as highly expressed in a subpopulation of tumor cells resistant to multiple commonly used chemotherapy drugs, as well as ST3GAL2, the rate-limiting enzyme of SSEA4 synthesis, as a predictive marker of poor outcome for breast and ovarian cancer patients undergoing chemotherapy. Both biomarkers and additionally identified regulatory miRNAs may be used to further understand chemoresistance, to stratify patient groups in order to avoid ineffective and painful therapies, and to develop alternative treatment regimens for breast cancer patients. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13058-015-0652-6) contains supplementary material, which is available to authorized users.
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spelling pubmed-46607832015-11-27 The sialyl-glycolipid stage-specific embryonic antigen 4 marks a subpopulation of chemotherapy-resistant breast cancer cells with mesenchymal features Aloia, Andrea Petrova, Evgeniya Tomiuk, Stefan Bissels, Ute Déas, Olivier Saini, Massimo Zickgraf, Franziska Maria Wagner, Steve Spaich, Saskia Sütterlin, Marc Schneeweiss, Andreas Reitberger, Manuel Rüberg, Silvia Gerstmayer, Bernhard Agorku, David Knöbel, Sebastian Terranegra, Annalisa Falleni, Monica Soldati, Laura Sprick, Martin Ronald Trumpp, Andreas Judde, Jean-Gabriel Bosio, Andreas Cairo, Stefano Hardt, Olaf Breast Cancer Res Research Article INTRODUCTION: Chemotherapy resistance resulting in incomplete pathologic response is associated with high risk of metastasis and early relapse in breast cancer. The aim of this study was to identify and evaluate biomarkers of treatment-resistant tumor cells. METHODS: We performed a cell surface marker screen in triple-negative breast cancer patient-derived xenograft models treated with standard care genotoxic chemotherapy. Global expression profiling was used to further characterize the identified treatment-resistant subpopulations. RESULTS: High expression of sialyl-glycolipid stage-specific embryonic antigen 4 (SSEA4) was found in residual tumor cells surviving chemotherapy and in samples from metastatic patients who relapsed after neoadjuvant chemotherapy. Gene and microRNA (miRNA) expression profiling linked SSEA4 positivity with a mesenchymal phenotype and a deregulation of drug resistance pathways. Functional assays demonstrated a direct link between epithelial–mesenchymal transition (EMT) and SSEA4 expression. Interestingly, SSEA4 expression, EMT, and drug resistance seemed to be regulated posttranscriptionally. Finally, high expression of CMP-N-acetylneuraminate-β-galactosamide-α-2,3-sialyltransferase 2 (ST3GAL2), the rate-limiting enzyme of SSEA4 synthesis, was found to be associated with poor clinical outcome in breast and ovarian cancer patients treated with chemotherapy. CONCLUSIONS: In this study, we identified SSEA4 as highly expressed in a subpopulation of tumor cells resistant to multiple commonly used chemotherapy drugs, as well as ST3GAL2, the rate-limiting enzyme of SSEA4 synthesis, as a predictive marker of poor outcome for breast and ovarian cancer patients undergoing chemotherapy. Both biomarkers and additionally identified regulatory miRNAs may be used to further understand chemoresistance, to stratify patient groups in order to avoid ineffective and painful therapies, and to develop alternative treatment regimens for breast cancer patients. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13058-015-0652-6) contains supplementary material, which is available to authorized users. BioMed Central 2015-11-25 2015 /pmc/articles/PMC4660783/ /pubmed/26607327 http://dx.doi.org/10.1186/s13058-015-0652-6 Text en © Aloia et al. 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Aloia, Andrea
Petrova, Evgeniya
Tomiuk, Stefan
Bissels, Ute
Déas, Olivier
Saini, Massimo
Zickgraf, Franziska Maria
Wagner, Steve
Spaich, Saskia
Sütterlin, Marc
Schneeweiss, Andreas
Reitberger, Manuel
Rüberg, Silvia
Gerstmayer, Bernhard
Agorku, David
Knöbel, Sebastian
Terranegra, Annalisa
Falleni, Monica
Soldati, Laura
Sprick, Martin Ronald
Trumpp, Andreas
Judde, Jean-Gabriel
Bosio, Andreas
Cairo, Stefano
Hardt, Olaf
The sialyl-glycolipid stage-specific embryonic antigen 4 marks a subpopulation of chemotherapy-resistant breast cancer cells with mesenchymal features
title The sialyl-glycolipid stage-specific embryonic antigen 4 marks a subpopulation of chemotherapy-resistant breast cancer cells with mesenchymal features
title_full The sialyl-glycolipid stage-specific embryonic antigen 4 marks a subpopulation of chemotherapy-resistant breast cancer cells with mesenchymal features
title_fullStr The sialyl-glycolipid stage-specific embryonic antigen 4 marks a subpopulation of chemotherapy-resistant breast cancer cells with mesenchymal features
title_full_unstemmed The sialyl-glycolipid stage-specific embryonic antigen 4 marks a subpopulation of chemotherapy-resistant breast cancer cells with mesenchymal features
title_short The sialyl-glycolipid stage-specific embryonic antigen 4 marks a subpopulation of chemotherapy-resistant breast cancer cells with mesenchymal features
title_sort sialyl-glycolipid stage-specific embryonic antigen 4 marks a subpopulation of chemotherapy-resistant breast cancer cells with mesenchymal features
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4660783/
https://www.ncbi.nlm.nih.gov/pubmed/26607327
http://dx.doi.org/10.1186/s13058-015-0652-6
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