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Targeting EphA2 impairs cell cycle progression and growth of basal-like/triple-negative breast cancers

Basal-like/triple-negative breast cancers (TNBCs) are among the most aggressive forms of breast cancer, and disproportionally affects young premenopausal women and women of African descent. Patients with TNBC suffer a poor prognosis due in part to a lack of molecularly targeted therapies, which repr...

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Autores principales: Song, W, Hwang, Y, Youngblood, V M, Cook, R S, Balko, J M, Chen, J, Brantley-Sieders, D M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5629103/
https://www.ncbi.nlm.nih.gov/pubmed/28581527
http://dx.doi.org/10.1038/onc.2017.170
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author Song, W
Hwang, Y
Youngblood, V M
Cook, R S
Balko, J M
Chen, J
Brantley-Sieders, D M
author_facet Song, W
Hwang, Y
Youngblood, V M
Cook, R S
Balko, J M
Chen, J
Brantley-Sieders, D M
author_sort Song, W
collection PubMed
description Basal-like/triple-negative breast cancers (TNBCs) are among the most aggressive forms of breast cancer, and disproportionally affects young premenopausal women and women of African descent. Patients with TNBC suffer a poor prognosis due in part to a lack of molecularly targeted therapies, which represents a critical barrier for effective treatment. Here, we identify EphA2 receptor tyrosine kinase as a clinically relevant target for TNBC. EphA2 expression is enriched in the basal-like molecular subtype in human breast cancers. Loss of EphA2 function in both human and genetically engineered mouse models of TNBC reduced tumor growth in culture and in vivo. Mechanistically, targeting EphA2 impaired cell cycle progression through S-phase via downregulation of c-Myc and stabilization of the cyclin-dependent kinase inhibitor p27/KIP1. A small molecule kinase inhibitor of EphA2 effectively suppressed tumor cell growth in vivo, including TNBC patient-derived xenografts. Thus, our data identify EphA2 as a novel molecular target for TNBC.
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spelling pubmed-56291032017-10-11 Targeting EphA2 impairs cell cycle progression and growth of basal-like/triple-negative breast cancers Song, W Hwang, Y Youngblood, V M Cook, R S Balko, J M Chen, J Brantley-Sieders, D M Oncogene Original Article Basal-like/triple-negative breast cancers (TNBCs) are among the most aggressive forms of breast cancer, and disproportionally affects young premenopausal women and women of African descent. Patients with TNBC suffer a poor prognosis due in part to a lack of molecularly targeted therapies, which represents a critical barrier for effective treatment. Here, we identify EphA2 receptor tyrosine kinase as a clinically relevant target for TNBC. EphA2 expression is enriched in the basal-like molecular subtype in human breast cancers. Loss of EphA2 function in both human and genetically engineered mouse models of TNBC reduced tumor growth in culture and in vivo. Mechanistically, targeting EphA2 impaired cell cycle progression through S-phase via downregulation of c-Myc and stabilization of the cyclin-dependent kinase inhibitor p27/KIP1. A small molecule kinase inhibitor of EphA2 effectively suppressed tumor cell growth in vivo, including TNBC patient-derived xenografts. Thus, our data identify EphA2 as a novel molecular target for TNBC. Nature Publishing Group 2017-10-05 2017-06-05 /pmc/articles/PMC5629103/ /pubmed/28581527 http://dx.doi.org/10.1038/onc.2017.170 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by-nc-sa/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/
spellingShingle Original Article
Song, W
Hwang, Y
Youngblood, V M
Cook, R S
Balko, J M
Chen, J
Brantley-Sieders, D M
Targeting EphA2 impairs cell cycle progression and growth of basal-like/triple-negative breast cancers
title Targeting EphA2 impairs cell cycle progression and growth of basal-like/triple-negative breast cancers
title_full Targeting EphA2 impairs cell cycle progression and growth of basal-like/triple-negative breast cancers
title_fullStr Targeting EphA2 impairs cell cycle progression and growth of basal-like/triple-negative breast cancers
title_full_unstemmed Targeting EphA2 impairs cell cycle progression and growth of basal-like/triple-negative breast cancers
title_short Targeting EphA2 impairs cell cycle progression and growth of basal-like/triple-negative breast cancers
title_sort targeting epha2 impairs cell cycle progression and growth of basal-like/triple-negative breast cancers
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5629103/
https://www.ncbi.nlm.nih.gov/pubmed/28581527
http://dx.doi.org/10.1038/onc.2017.170
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