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The role of the desmosomal protein desmocollin 2 in tumour progression in triple negative breast cancer patients
BACKGROUND: The disruption of epithelial features represents a critical step during breast cancer spread. In this context, the dysregulation of desmosomal proteins has been associated with malignant progression and metastasis formation. Curiously, both tumour suppressive and pro-metastatic roles hav...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10018948/ https://www.ncbi.nlm.nih.gov/pubmed/36927383 http://dx.doi.org/10.1186/s12935-023-02896-9 |
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author | Reimer, Francesca Bryan, Sarah Legler, Karen Karn, Thomas Eppenberger-Castori, Serenella Matschke, Jakob Pereira-Veiga, Thais Wikman, Harriet Witzel, Isabell Müller, Volkmar Schmalfeldt, Barbara Milde-Langosch, Karin Schumacher, Udo Stürken, Christine Oliveira-Ferrer, Leticia |
author_facet | Reimer, Francesca Bryan, Sarah Legler, Karen Karn, Thomas Eppenberger-Castori, Serenella Matschke, Jakob Pereira-Veiga, Thais Wikman, Harriet Witzel, Isabell Müller, Volkmar Schmalfeldt, Barbara Milde-Langosch, Karin Schumacher, Udo Stürken, Christine Oliveira-Ferrer, Leticia |
author_sort | Reimer, Francesca |
collection | PubMed |
description | BACKGROUND: The disruption of epithelial features represents a critical step during breast cancer spread. In this context, the dysregulation of desmosomal proteins has been associated with malignant progression and metastasis formation. Curiously, both tumour suppressive and pro-metastatic roles have been attributed to desmosomal structures in different cancer entities. In the present study, we describe the pro-metastatic role of the desmosomal protein desmocollin 2 (DSC2) in breast cancer. METHODS: We analysed the prognostic role of DSC2 at mRNA and protein level using microarray data, western blot analysis and immunohistochemistry. Functional consequences of DSC2 overexpression and DSC2 knock down were investigated in the triple negative breast cancer (TNBC) cell line MDA-MB-231 and its brain-seeking subline MDA-MB-231-BR, respectively in vitro and in vivo. RESULTS: We found a significantly higher DSC2 expression in the more aggressive molecular subtypes HER2-positive and TNBC than in luminal breast cancers, as well as a significant correlation between increased DSC2 expression and a shorter disease-free—also in multivariate analysis—and overall survival. Additionally, a significant association between DSC2 expression in the primary tumour and an increased frequency of cerebral and lung metastasis could be observed. In vitro, ectopic DSC2 expression or DSC2 down-regulation in MDA-MB-231 and MDA-MB-231-BR led to a significant tumour cell aggregation increase and decrease, respectively. Furthermore, tumour cells displaying higher DSC2 levels showed increased chemoresistance in 3D structures, but not 2D monolayer structures, suggesting the importance of cell aggregation as a means for reduced drug diffusion. In an in vivo brain dissemination xenograft mouse model, reduced expression of DSC2 in the brain-seeking TNBC cells led to a decreased amount of circulating tumour cells/clusters and, in turn, to fewer and smaller brain metastatic lesions. CONCLUSION: We conclude that high DSC2 expression in primary TNBC is associated with a poorer prognosis, firstly by increasing tumour cell aggregation, secondly by reducing the diffusion and effectiveness of chemotherapeutic agents, and, lastly, by promoting the circulation and survival of tumour cell clusters, each of which facilitates distant organ colonisation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12935-023-02896-9. |
format | Online Article Text |
id | pubmed-10018948 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-100189482023-03-17 The role of the desmosomal protein desmocollin 2 in tumour progression in triple negative breast cancer patients Reimer, Francesca Bryan, Sarah Legler, Karen Karn, Thomas Eppenberger-Castori, Serenella Matschke, Jakob Pereira-Veiga, Thais Wikman, Harriet Witzel, Isabell Müller, Volkmar Schmalfeldt, Barbara Milde-Langosch, Karin Schumacher, Udo Stürken, Christine Oliveira-Ferrer, Leticia Cancer Cell Int Research BACKGROUND: The disruption of epithelial features represents a critical step during breast cancer spread. In this context, the dysregulation of desmosomal proteins has been associated with malignant progression and metastasis formation. Curiously, both tumour suppressive and pro-metastatic roles have been attributed to desmosomal structures in different cancer entities. In the present study, we describe the pro-metastatic role of the desmosomal protein desmocollin 2 (DSC2) in breast cancer. METHODS: We analysed the prognostic role of DSC2 at mRNA and protein level using microarray data, western blot analysis and immunohistochemistry. Functional consequences of DSC2 overexpression and DSC2 knock down were investigated in the triple negative breast cancer (TNBC) cell line MDA-MB-231 and its brain-seeking subline MDA-MB-231-BR, respectively in vitro and in vivo. RESULTS: We found a significantly higher DSC2 expression in the more aggressive molecular subtypes HER2-positive and TNBC than in luminal breast cancers, as well as a significant correlation between increased DSC2 expression and a shorter disease-free—also in multivariate analysis—and overall survival. Additionally, a significant association between DSC2 expression in the primary tumour and an increased frequency of cerebral and lung metastasis could be observed. In vitro, ectopic DSC2 expression or DSC2 down-regulation in MDA-MB-231 and MDA-MB-231-BR led to a significant tumour cell aggregation increase and decrease, respectively. Furthermore, tumour cells displaying higher DSC2 levels showed increased chemoresistance in 3D structures, but not 2D monolayer structures, suggesting the importance of cell aggregation as a means for reduced drug diffusion. In an in vivo brain dissemination xenograft mouse model, reduced expression of DSC2 in the brain-seeking TNBC cells led to a decreased amount of circulating tumour cells/clusters and, in turn, to fewer and smaller brain metastatic lesions. CONCLUSION: We conclude that high DSC2 expression in primary TNBC is associated with a poorer prognosis, firstly by increasing tumour cell aggregation, secondly by reducing the diffusion and effectiveness of chemotherapeutic agents, and, lastly, by promoting the circulation and survival of tumour cell clusters, each of which facilitates distant organ colonisation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12935-023-02896-9. BioMed Central 2023-03-16 /pmc/articles/PMC10018948/ /pubmed/36927383 http://dx.doi.org/10.1186/s12935-023-02896-9 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Reimer, Francesca Bryan, Sarah Legler, Karen Karn, Thomas Eppenberger-Castori, Serenella Matschke, Jakob Pereira-Veiga, Thais Wikman, Harriet Witzel, Isabell Müller, Volkmar Schmalfeldt, Barbara Milde-Langosch, Karin Schumacher, Udo Stürken, Christine Oliveira-Ferrer, Leticia The role of the desmosomal protein desmocollin 2 in tumour progression in triple negative breast cancer patients |
title | The role of the desmosomal protein desmocollin 2 in tumour progression in triple negative breast cancer patients |
title_full | The role of the desmosomal protein desmocollin 2 in tumour progression in triple negative breast cancer patients |
title_fullStr | The role of the desmosomal protein desmocollin 2 in tumour progression in triple negative breast cancer patients |
title_full_unstemmed | The role of the desmosomal protein desmocollin 2 in tumour progression in triple negative breast cancer patients |
title_short | The role of the desmosomal protein desmocollin 2 in tumour progression in triple negative breast cancer patients |
title_sort | role of the desmosomal protein desmocollin 2 in tumour progression in triple negative breast cancer patients |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10018948/ https://www.ncbi.nlm.nih.gov/pubmed/36927383 http://dx.doi.org/10.1186/s12935-023-02896-9 |
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