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The Hippo Pathway Transducers YAP1/TEAD Induce Acquired Resistance to Trastuzumab in HER2-Positive Breast Cancer

Trastuzumab is the first-line targeted therapeutic drug for HER2-positive breast cancer, leading to improved overall survival. However, acquired resistance inevitably occurs. We aimed to identify, quantify, and assess the mechanisms of acquired resistance to trastuzumab. We established an acquired t...

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Autores principales: González-Alonso, Paula, Zazo, Sandra, Martín-Aparicio, Ester, Luque, Melani, Chamizo, Cristina, Sanz-Álvarez, Marta, Minguez, Pablo, Gómez-López, Gonzalo, Cristóbal, Ion, Caramés, Cristina, García-Foncillas, Jesús, Eroles, Pilar, Lluch, Ana, Arpí, Oriol, Rovira, Ana, Albanell, Joan, Piersma, Sander R., Jimenez, Connie R., Madoz-Gúrpide, Juan, Rojo, Federico
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281325/
https://www.ncbi.nlm.nih.gov/pubmed/32365528
http://dx.doi.org/10.3390/cancers12051108
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author González-Alonso, Paula
Zazo, Sandra
Martín-Aparicio, Ester
Luque, Melani
Chamizo, Cristina
Sanz-Álvarez, Marta
Minguez, Pablo
Gómez-López, Gonzalo
Cristóbal, Ion
Caramés, Cristina
García-Foncillas, Jesús
Eroles, Pilar
Lluch, Ana
Arpí, Oriol
Rovira, Ana
Albanell, Joan
Piersma, Sander R.
Jimenez, Connie R.
Madoz-Gúrpide, Juan
Rojo, Federico
author_facet González-Alonso, Paula
Zazo, Sandra
Martín-Aparicio, Ester
Luque, Melani
Chamizo, Cristina
Sanz-Álvarez, Marta
Minguez, Pablo
Gómez-López, Gonzalo
Cristóbal, Ion
Caramés, Cristina
García-Foncillas, Jesús
Eroles, Pilar
Lluch, Ana
Arpí, Oriol
Rovira, Ana
Albanell, Joan
Piersma, Sander R.
Jimenez, Connie R.
Madoz-Gúrpide, Juan
Rojo, Federico
author_sort González-Alonso, Paula
collection PubMed
description Trastuzumab is the first-line targeted therapeutic drug for HER2-positive breast cancer, leading to improved overall survival. However, acquired resistance inevitably occurs. We aimed to identify, quantify, and assess the mechanisms of acquired resistance to trastuzumab. We established an acquired trastuzumab-resistant model in vitro from BT-474, a trastuzumab-sensitive, HER2-amplified breast-cancer cell line. A multi-omic strategy was implemented to obtain gene, proteome, and phosphoproteome signatures associated with acquired resistance to trastuzumab in HER2-positive breast cancer, followed by validation in human clinical samples. YAP1 dephosphorylation and TEAD2 overexpression were detected as significant alterations in the Hippo pathway in trastuzumab-resistant breast cancer. Because of the emerging role of these proteins as mediators of normal growth and tumorigenesis, we assessed the exogenous modulation of their activity, either by in vitro gene silencing or by pharmacological inhibition of the YAP1/TEAD complexes, both in vitro and in vivo. Moreover, we identified increased signaling through the Hippo pathway in human samples after progression following trastuzumab treatment. Finally, YAP1/TAZ nuclear accumulation in malignant cells in HER2 breast tumor was significantly associated with worse progression-free and overall survival in metastatic HER2-positive breast-cancer patients. Our results suggest the involvement of Hippo signaling in acquired trastuzumab resistance in breast cancer. Additionally, we provide novel evidence for a potential breast-cancer treatment strategy based on dual targeting of HER2 and Hippo pathway effectors, which may improve the antitumor activity of trastuzumab and help overcome resistance.
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spelling pubmed-72813252020-06-19 The Hippo Pathway Transducers YAP1/TEAD Induce Acquired Resistance to Trastuzumab in HER2-Positive Breast Cancer González-Alonso, Paula Zazo, Sandra Martín-Aparicio, Ester Luque, Melani Chamizo, Cristina Sanz-Álvarez, Marta Minguez, Pablo Gómez-López, Gonzalo Cristóbal, Ion Caramés, Cristina García-Foncillas, Jesús Eroles, Pilar Lluch, Ana Arpí, Oriol Rovira, Ana Albanell, Joan Piersma, Sander R. Jimenez, Connie R. Madoz-Gúrpide, Juan Rojo, Federico Cancers (Basel) Article Trastuzumab is the first-line targeted therapeutic drug for HER2-positive breast cancer, leading to improved overall survival. However, acquired resistance inevitably occurs. We aimed to identify, quantify, and assess the mechanisms of acquired resistance to trastuzumab. We established an acquired trastuzumab-resistant model in vitro from BT-474, a trastuzumab-sensitive, HER2-amplified breast-cancer cell line. A multi-omic strategy was implemented to obtain gene, proteome, and phosphoproteome signatures associated with acquired resistance to trastuzumab in HER2-positive breast cancer, followed by validation in human clinical samples. YAP1 dephosphorylation and TEAD2 overexpression were detected as significant alterations in the Hippo pathway in trastuzumab-resistant breast cancer. Because of the emerging role of these proteins as mediators of normal growth and tumorigenesis, we assessed the exogenous modulation of their activity, either by in vitro gene silencing or by pharmacological inhibition of the YAP1/TEAD complexes, both in vitro and in vivo. Moreover, we identified increased signaling through the Hippo pathway in human samples after progression following trastuzumab treatment. Finally, YAP1/TAZ nuclear accumulation in malignant cells in HER2 breast tumor was significantly associated with worse progression-free and overall survival in metastatic HER2-positive breast-cancer patients. Our results suggest the involvement of Hippo signaling in acquired trastuzumab resistance in breast cancer. Additionally, we provide novel evidence for a potential breast-cancer treatment strategy based on dual targeting of HER2 and Hippo pathway effectors, which may improve the antitumor activity of trastuzumab and help overcome resistance. MDPI 2020-04-29 /pmc/articles/PMC7281325/ /pubmed/32365528 http://dx.doi.org/10.3390/cancers12051108 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
González-Alonso, Paula
Zazo, Sandra
Martín-Aparicio, Ester
Luque, Melani
Chamizo, Cristina
Sanz-Álvarez, Marta
Minguez, Pablo
Gómez-López, Gonzalo
Cristóbal, Ion
Caramés, Cristina
García-Foncillas, Jesús
Eroles, Pilar
Lluch, Ana
Arpí, Oriol
Rovira, Ana
Albanell, Joan
Piersma, Sander R.
Jimenez, Connie R.
Madoz-Gúrpide, Juan
Rojo, Federico
The Hippo Pathway Transducers YAP1/TEAD Induce Acquired Resistance to Trastuzumab in HER2-Positive Breast Cancer
title The Hippo Pathway Transducers YAP1/TEAD Induce Acquired Resistance to Trastuzumab in HER2-Positive Breast Cancer
title_full The Hippo Pathway Transducers YAP1/TEAD Induce Acquired Resistance to Trastuzumab in HER2-Positive Breast Cancer
title_fullStr The Hippo Pathway Transducers YAP1/TEAD Induce Acquired Resistance to Trastuzumab in HER2-Positive Breast Cancer
title_full_unstemmed The Hippo Pathway Transducers YAP1/TEAD Induce Acquired Resistance to Trastuzumab in HER2-Positive Breast Cancer
title_short The Hippo Pathway Transducers YAP1/TEAD Induce Acquired Resistance to Trastuzumab in HER2-Positive Breast Cancer
title_sort hippo pathway transducers yap1/tead induce acquired resistance to trastuzumab in her2-positive breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281325/
https://www.ncbi.nlm.nih.gov/pubmed/32365528
http://dx.doi.org/10.3390/cancers12051108
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