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Modeling Heterogeneity of Triple‐Negative Breast Cancer Uncovers a Novel Combinatorial Treatment Overcoming Primary Drug Resistance
Triple‐negative breast cancer (TNBC) is a highly aggressive breast cancer subtype characterized by a remarkable molecular heterogeneity. Currently, there are no effective druggable targets and advanced preclinical models of the human disease. Here, a unique mouse model (MMTV‐R26(Met) mice) of mammar...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856896/ https://www.ncbi.nlm.nih.gov/pubmed/33552868 http://dx.doi.org/10.1002/advs.202003049 |
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author | Lamballe, Fabienne Ahmad, Fahmida Vinik, Yaron Castellanet, Olivier Daian, Fabrice Müller, Anna‐Katharina Köhler, Ulrike A. Bailly, Anne‐Laure Josselin, Emmanuelle Castellano, Rémy Cayrou, Christelle Charafe‐Jauffret, Emmanuelle Mills, Gordon B. Géli, Vincent Borg, Jean‐Paul Lev, Sima Maina, Flavio |
author_facet | Lamballe, Fabienne Ahmad, Fahmida Vinik, Yaron Castellanet, Olivier Daian, Fabrice Müller, Anna‐Katharina Köhler, Ulrike A. Bailly, Anne‐Laure Josselin, Emmanuelle Castellano, Rémy Cayrou, Christelle Charafe‐Jauffret, Emmanuelle Mills, Gordon B. Géli, Vincent Borg, Jean‐Paul Lev, Sima Maina, Flavio |
author_sort | Lamballe, Fabienne |
collection | PubMed |
description | Triple‐negative breast cancer (TNBC) is a highly aggressive breast cancer subtype characterized by a remarkable molecular heterogeneity. Currently, there are no effective druggable targets and advanced preclinical models of the human disease. Here, a unique mouse model (MMTV‐R26(Met) mice) of mammary tumors driven by a subtle increase in the expression of the wild‐type MET receptor is generated. MMTV‐R26(Met) mice develop spontaneous, exclusive TNBC tumors, recapitulating primary resistance to treatment of patients. Proteomic profiling of MMTV‐R26(Met) tumors and machine learning approach show that the model faithfully recapitulates intertumoral heterogeneity of human TNBC. Further signaling network analysis highlights potential druggable targets, of which cotargeting of WEE1 and BCL‐XL synergistically kills TNBC cells and efficiently induces tumor regression. Mechanistically, BCL‐XL inhibition exacerbates the dependency of TNBC cells on WEE1 function, leading to Histone H3 and phosphoS(33)RPA32 upregulation, RRM2 downregulation, cell cycle perturbation, mitotic catastrophe, and apoptosis. This study introduces a unique, powerful mouse model for studying TNBC formation and evolution, its heterogeneity, and for identifying efficient therapeutic targets. |
format | Online Article Text |
id | pubmed-7856896 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-78568962021-02-05 Modeling Heterogeneity of Triple‐Negative Breast Cancer Uncovers a Novel Combinatorial Treatment Overcoming Primary Drug Resistance Lamballe, Fabienne Ahmad, Fahmida Vinik, Yaron Castellanet, Olivier Daian, Fabrice Müller, Anna‐Katharina Köhler, Ulrike A. Bailly, Anne‐Laure Josselin, Emmanuelle Castellano, Rémy Cayrou, Christelle Charafe‐Jauffret, Emmanuelle Mills, Gordon B. Géli, Vincent Borg, Jean‐Paul Lev, Sima Maina, Flavio Adv Sci (Weinh) Full Papers Triple‐negative breast cancer (TNBC) is a highly aggressive breast cancer subtype characterized by a remarkable molecular heterogeneity. Currently, there are no effective druggable targets and advanced preclinical models of the human disease. Here, a unique mouse model (MMTV‐R26(Met) mice) of mammary tumors driven by a subtle increase in the expression of the wild‐type MET receptor is generated. MMTV‐R26(Met) mice develop spontaneous, exclusive TNBC tumors, recapitulating primary resistance to treatment of patients. Proteomic profiling of MMTV‐R26(Met) tumors and machine learning approach show that the model faithfully recapitulates intertumoral heterogeneity of human TNBC. Further signaling network analysis highlights potential druggable targets, of which cotargeting of WEE1 and BCL‐XL synergistically kills TNBC cells and efficiently induces tumor regression. Mechanistically, BCL‐XL inhibition exacerbates the dependency of TNBC cells on WEE1 function, leading to Histone H3 and phosphoS(33)RPA32 upregulation, RRM2 downregulation, cell cycle perturbation, mitotic catastrophe, and apoptosis. This study introduces a unique, powerful mouse model for studying TNBC formation and evolution, its heterogeneity, and for identifying efficient therapeutic targets. John Wiley and Sons Inc. 2020-12-16 /pmc/articles/PMC7856896/ /pubmed/33552868 http://dx.doi.org/10.1002/advs.202003049 Text en © 2020 The Authors. Advanced Science published by Wiley‐VCH GmbH This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Full Papers Lamballe, Fabienne Ahmad, Fahmida Vinik, Yaron Castellanet, Olivier Daian, Fabrice Müller, Anna‐Katharina Köhler, Ulrike A. Bailly, Anne‐Laure Josselin, Emmanuelle Castellano, Rémy Cayrou, Christelle Charafe‐Jauffret, Emmanuelle Mills, Gordon B. Géli, Vincent Borg, Jean‐Paul Lev, Sima Maina, Flavio Modeling Heterogeneity of Triple‐Negative Breast Cancer Uncovers a Novel Combinatorial Treatment Overcoming Primary Drug Resistance |
title | Modeling Heterogeneity of Triple‐Negative Breast Cancer Uncovers a Novel Combinatorial Treatment Overcoming Primary Drug Resistance |
title_full | Modeling Heterogeneity of Triple‐Negative Breast Cancer Uncovers a Novel Combinatorial Treatment Overcoming Primary Drug Resistance |
title_fullStr | Modeling Heterogeneity of Triple‐Negative Breast Cancer Uncovers a Novel Combinatorial Treatment Overcoming Primary Drug Resistance |
title_full_unstemmed | Modeling Heterogeneity of Triple‐Negative Breast Cancer Uncovers a Novel Combinatorial Treatment Overcoming Primary Drug Resistance |
title_short | Modeling Heterogeneity of Triple‐Negative Breast Cancer Uncovers a Novel Combinatorial Treatment Overcoming Primary Drug Resistance |
title_sort | modeling heterogeneity of triple‐negative breast cancer uncovers a novel combinatorial treatment overcoming primary drug resistance |
topic | Full Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856896/ https://www.ncbi.nlm.nih.gov/pubmed/33552868 http://dx.doi.org/10.1002/advs.202003049 |
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