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Loss of E-cadherin leads to Id2-dependent inhibition of cell cycle progression in metastatic lobular breast cancer
Invasive lobular breast carcinoma (ILC) is characterized by proliferative indolence and long-term latency relapses. This study aimed to identify how disseminating ILC cells control the balance between quiescence and cell cycle re-entry. In the absence of anchorage, ILC cells undergo a sustained cell...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9122823/ https://www.ncbi.nlm.nih.gov/pubmed/35437308 http://dx.doi.org/10.1038/s41388-022-02314-w |
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author | Rätze, Max A. K. Koorman, Thijs Sijnesael, Thijmen Bassey-Archibong, Blessing van de Ven, Robert Enserink, Lotte Visser, Daan Jaksani, Sridevi Viciano, Ignacio Bakker, Elvira R. M. Richard, François Tutt, Andrew O’Leary, Lynda Fitzpatrick, Amanda Roca-Cusachs, Pere van Diest, Paul J. Desmedt, Christine Daniel, Juliet M. Isacke, Clare M. Derksen, Patrick W. B. |
author_facet | Rätze, Max A. K. Koorman, Thijs Sijnesael, Thijmen Bassey-Archibong, Blessing van de Ven, Robert Enserink, Lotte Visser, Daan Jaksani, Sridevi Viciano, Ignacio Bakker, Elvira R. M. Richard, François Tutt, Andrew O’Leary, Lynda Fitzpatrick, Amanda Roca-Cusachs, Pere van Diest, Paul J. Desmedt, Christine Daniel, Juliet M. Isacke, Clare M. Derksen, Patrick W. B. |
author_sort | Rätze, Max A. K. |
collection | PubMed |
description | Invasive lobular breast carcinoma (ILC) is characterized by proliferative indolence and long-term latency relapses. This study aimed to identify how disseminating ILC cells control the balance between quiescence and cell cycle re-entry. In the absence of anchorage, ILC cells undergo a sustained cell cycle arrest in G0/G1 while maintaining viability. From the genes that are upregulated in anchorage independent ILC cells, we selected Inhibitor of DNA binding 2 (Id2), a mediator of cell cycle progression. Using loss-of-function experiments, we demonstrate that Id2 is essential for anchorage independent survival (anoikis resistance) in vitro and lung colonization in mice. Importantly, we find that under anchorage independent conditions, E-cadherin loss promotes expression of Id2 in multiple mouse and (organotypic) human models of ILC, an event that is caused by a direct p120-catenin/Kaiso-dependent transcriptional de-repression of the canonical Kaiso binding sequence TCCTGCNA. Conversely, stable inducible restoration of E-cadherin expression in the ILC cell line SUM44PE inhibits Id2 expression and anoikis resistance. We show evidence that Id2 accumulates in the cytosol, where it induces a sustained and CDK4/6-dependent G0/G1 cell cycle arrest through interaction with hypo-phosphorylated Rb. Finally, we find that Id2 is indeed enriched in ILC when compared to other breast cancers, and confirm cytosolic Id2 protein expression in primary ILC samples. In sum, we have linked mutational inactivation of E-cadherin to direct inhibition of cell cycle progression. Our work indicates that loss of E-cadherin and subsequent expression of Id2 drive indolence and dissemination of ILC. As such, E-cadherin and Id2 are promising candidates to stratify low and intermediate grade invasive breast cancers for the use of clinical cell cycle intervention drugs. |
format | Online Article Text |
id | pubmed-9122823 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-91228232022-05-22 Loss of E-cadherin leads to Id2-dependent inhibition of cell cycle progression in metastatic lobular breast cancer Rätze, Max A. K. Koorman, Thijs Sijnesael, Thijmen Bassey-Archibong, Blessing van de Ven, Robert Enserink, Lotte Visser, Daan Jaksani, Sridevi Viciano, Ignacio Bakker, Elvira R. M. Richard, François Tutt, Andrew O’Leary, Lynda Fitzpatrick, Amanda Roca-Cusachs, Pere van Diest, Paul J. Desmedt, Christine Daniel, Juliet M. Isacke, Clare M. Derksen, Patrick W. B. Oncogene Article Invasive lobular breast carcinoma (ILC) is characterized by proliferative indolence and long-term latency relapses. This study aimed to identify how disseminating ILC cells control the balance between quiescence and cell cycle re-entry. In the absence of anchorage, ILC cells undergo a sustained cell cycle arrest in G0/G1 while maintaining viability. From the genes that are upregulated in anchorage independent ILC cells, we selected Inhibitor of DNA binding 2 (Id2), a mediator of cell cycle progression. Using loss-of-function experiments, we demonstrate that Id2 is essential for anchorage independent survival (anoikis resistance) in vitro and lung colonization in mice. Importantly, we find that under anchorage independent conditions, E-cadherin loss promotes expression of Id2 in multiple mouse and (organotypic) human models of ILC, an event that is caused by a direct p120-catenin/Kaiso-dependent transcriptional de-repression of the canonical Kaiso binding sequence TCCTGCNA. Conversely, stable inducible restoration of E-cadherin expression in the ILC cell line SUM44PE inhibits Id2 expression and anoikis resistance. We show evidence that Id2 accumulates in the cytosol, where it induces a sustained and CDK4/6-dependent G0/G1 cell cycle arrest through interaction with hypo-phosphorylated Rb. Finally, we find that Id2 is indeed enriched in ILC when compared to other breast cancers, and confirm cytosolic Id2 protein expression in primary ILC samples. In sum, we have linked mutational inactivation of E-cadherin to direct inhibition of cell cycle progression. Our work indicates that loss of E-cadherin and subsequent expression of Id2 drive indolence and dissemination of ILC. As such, E-cadherin and Id2 are promising candidates to stratify low and intermediate grade invasive breast cancers for the use of clinical cell cycle intervention drugs. Nature Publishing Group UK 2022-04-18 2022 /pmc/articles/PMC9122823/ /pubmed/35437308 http://dx.doi.org/10.1038/s41388-022-02314-w Text en © The Author(s) 2022, corrected publication 2022 https://creativecommons.org/licenses/by/4.0/Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Rätze, Max A. K. Koorman, Thijs Sijnesael, Thijmen Bassey-Archibong, Blessing van de Ven, Robert Enserink, Lotte Visser, Daan Jaksani, Sridevi Viciano, Ignacio Bakker, Elvira R. M. Richard, François Tutt, Andrew O’Leary, Lynda Fitzpatrick, Amanda Roca-Cusachs, Pere van Diest, Paul J. Desmedt, Christine Daniel, Juliet M. Isacke, Clare M. Derksen, Patrick W. B. Loss of E-cadherin leads to Id2-dependent inhibition of cell cycle progression in metastatic lobular breast cancer |
title | Loss of E-cadherin leads to Id2-dependent inhibition of cell cycle progression in metastatic lobular breast cancer |
title_full | Loss of E-cadherin leads to Id2-dependent inhibition of cell cycle progression in metastatic lobular breast cancer |
title_fullStr | Loss of E-cadherin leads to Id2-dependent inhibition of cell cycle progression in metastatic lobular breast cancer |
title_full_unstemmed | Loss of E-cadherin leads to Id2-dependent inhibition of cell cycle progression in metastatic lobular breast cancer |
title_short | Loss of E-cadherin leads to Id2-dependent inhibition of cell cycle progression in metastatic lobular breast cancer |
title_sort | loss of e-cadherin leads to id2-dependent inhibition of cell cycle progression in metastatic lobular breast cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9122823/ https://www.ncbi.nlm.nih.gov/pubmed/35437308 http://dx.doi.org/10.1038/s41388-022-02314-w |
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