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Generation, characterization, and maintenance of trastuzumab-resistant HER2+ breast cancer cell lines

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dc.contributor.author Zazo, Sandra
dc.contributor.author González-Alonso, Paula
dc.contributor.author Martín-Aparicio, Ester
dc.contributor.author Chamizo, Cristina
dc.contributor.author Cristóbal, Ion
dc.contributor.author Arpí Llucià, Oriol
dc.contributor.author Rovira Guerín, Ana
dc.contributor.author Albanell Mestres, Joan
dc.contributor.author Eroles, Pilar
dc.contributor.author Lluch, Ana
dc.contributor.author Madoz-Gúrpide, Juan
dc.contributor.author Rojo, Federico
dc.date.accessioned 2018-01-22T08:43:40Z
dc.date.available 2018-01-22T08:43:40Z
dc.date.issued 2017
dc.identifier.citation Zazo S, González-Alonso P, Martín-Aparicio E, Chamizo C, Cristóbal I, Arpí O. et al. Generation, characterization, and maintenance of trastuzumab-resistant HER2+ breast cancer cell lines. Am J Cancer Res. 2016 Nov 1;6(11):2661-2678
dc.identifier.uri http://hdl.handle.net/10230/33707
dc.description.abstract Trastuzumab became the therapy of choice for patients with HER2-positive breast cancer in 1998, and it has provided clinical benefit ever since. However, a significant percentage of patients show primary resistance to trastuzumab at diagnosis, and most patients with metastatic disease that initially respond to trastuzumab eventually progress (acquired resistance). Consequently, there is an urgent need to improve our knowledge of the mechanisms governing resistance, so that specific therapeutic strategies can be developed to provide improved efficacy. We generated new cell lines derived from BCCL through extended exposure to trastuzumab. Drug-conditioned populations were authenticated for their molecular profile and their resistance rate was determined. Heterogeneous HER2 amplification was observed across most of the BCCLs, ranging from cells without HER2 amplification to elevated HER2 gene copy numbers in others. Using a phospho-antibody array we analyzed the status of kinase receptors and effectors from different cellular pathways. This revealed that HER2, AKT, and S6RP presented high phosphorylation levels with specific variations between sensitive and resistant populations. In addition, differences in phosphorylation levels for several of those pathways targets were found between sensitive and resistant lines. Furthermore, a biochemical study characterized patterns of molecular alterations similar to those commonly described in breast cancer. Finally, a subcutaneous xenograft murine model confirmed the resistance to trastuzumab of the established cell line. We conclude that these resistant BCCLs can be a valuable tool to gain insight into the mechanisms of acquisition of trastuzumab resistance.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher e-Century Publishing
dc.rights AJCR Copyright © 2016
dc.subject.other Mama -- Càncer -- Tractament
dc.title Generation, characterization, and maintenance of trastuzumab-resistant HER2+ breast cancer cell lines
dc.type info:eu-repo/semantics/article
dc.subject.keyword Breast cancer
dc.subject.keyword Anti-receptor therapy
dc.subject.keyword Cell lines
dc.subject.keyword Resistance
dc.subject.keyword Trastuzumab
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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