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Tamoxifen-resistant breast cancer cells are resistant to DNA-damaging chemotherapy because of upregulated BARD1 and BRCA1

Tamoxifen resistance is accountable for relapse in many ER-positive breast cancer patients. Most of these recurrent patients receive chemotherapy, but their chemosensitivity is unknown. Here, we report that tamoxifen-resistant breast cancer cells express significantly more BARD1 and BRCA1, leading t...

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Autores principales: Zhu, Yinghua, Liu, Yujie, Zhang, Chao, Chu, Junjun, Wu, Yanqing, Li, Yudong, Liu, Jieqiong, Li, Qian, Li, Shunying, Shi, Qianfeng, Jin, Liang, Zhao, Jianli, Yin, Dong, Efroni, Sol, Su, Fengxi, Yao, Herui, Song, Erwei, Liu, Qiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5913295/
https://www.ncbi.nlm.nih.gov/pubmed/29686231
http://dx.doi.org/10.1038/s41467-018-03951-0
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author Zhu, Yinghua
Liu, Yujie
Zhang, Chao
Chu, Junjun
Wu, Yanqing
Li, Yudong
Liu, Jieqiong
Li, Qian
Li, Shunying
Shi, Qianfeng
Jin, Liang
Zhao, Jianli
Yin, Dong
Efroni, Sol
Su, Fengxi
Yao, Herui
Song, Erwei
Liu, Qiang
author_facet Zhu, Yinghua
Liu, Yujie
Zhang, Chao
Chu, Junjun
Wu, Yanqing
Li, Yudong
Liu, Jieqiong
Li, Qian
Li, Shunying
Shi, Qianfeng
Jin, Liang
Zhao, Jianli
Yin, Dong
Efroni, Sol
Su, Fengxi
Yao, Herui
Song, Erwei
Liu, Qiang
author_sort Zhu, Yinghua
collection PubMed
description Tamoxifen resistance is accountable for relapse in many ER-positive breast cancer patients. Most of these recurrent patients receive chemotherapy, but their chemosensitivity is unknown. Here, we report that tamoxifen-resistant breast cancer cells express significantly more BARD1 and BRCA1, leading to resistance to DNA-damaging chemotherapy including cisplatin and adriamycin, but not to paclitaxel. Silencing BARD1 or BRCA1 expression or inhibition of BRCA1 phosphorylation by Dinaciclib restores the sensitivity to cisplatin in tamoxifen-resistant cells. Furthermore, we show that activated PI3K/AKT pathway is responsible for the upregulation of BARD1 and BRCA1. PI3K inhibitors decrease the expression of BARD1 and BRCA1 in tamoxifen-resistant cells and re-sensitize them to cisplatin both in vitro and in vivo. Higher BARD1 and BRCA1 expression is associated with worse prognosis of early breast cancer patients, especially the ones that received radiotherapy, indicating the potential use of PI3K inhibitors to reverse chemoresistance and radioresistance in ER-positive breast cancer patients.
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spelling pubmed-59132952018-04-25 Tamoxifen-resistant breast cancer cells are resistant to DNA-damaging chemotherapy because of upregulated BARD1 and BRCA1 Zhu, Yinghua Liu, Yujie Zhang, Chao Chu, Junjun Wu, Yanqing Li, Yudong Liu, Jieqiong Li, Qian Li, Shunying Shi, Qianfeng Jin, Liang Zhao, Jianli Yin, Dong Efroni, Sol Su, Fengxi Yao, Herui Song, Erwei Liu, Qiang Nat Commun Article Tamoxifen resistance is accountable for relapse in many ER-positive breast cancer patients. Most of these recurrent patients receive chemotherapy, but their chemosensitivity is unknown. Here, we report that tamoxifen-resistant breast cancer cells express significantly more BARD1 and BRCA1, leading to resistance to DNA-damaging chemotherapy including cisplatin and adriamycin, but not to paclitaxel. Silencing BARD1 or BRCA1 expression or inhibition of BRCA1 phosphorylation by Dinaciclib restores the sensitivity to cisplatin in tamoxifen-resistant cells. Furthermore, we show that activated PI3K/AKT pathway is responsible for the upregulation of BARD1 and BRCA1. PI3K inhibitors decrease the expression of BARD1 and BRCA1 in tamoxifen-resistant cells and re-sensitize them to cisplatin both in vitro and in vivo. Higher BARD1 and BRCA1 expression is associated with worse prognosis of early breast cancer patients, especially the ones that received radiotherapy, indicating the potential use of PI3K inhibitors to reverse chemoresistance and radioresistance in ER-positive breast cancer patients. Nature Publishing Group UK 2018-04-23 /pmc/articles/PMC5913295/ /pubmed/29686231 http://dx.doi.org/10.1038/s41467-018-03951-0 Text en © The Author(s) 2018 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/.
spellingShingle Article
Zhu, Yinghua
Liu, Yujie
Zhang, Chao
Chu, Junjun
Wu, Yanqing
Li, Yudong
Liu, Jieqiong
Li, Qian
Li, Shunying
Shi, Qianfeng
Jin, Liang
Zhao, Jianli
Yin, Dong
Efroni, Sol
Su, Fengxi
Yao, Herui
Song, Erwei
Liu, Qiang
Tamoxifen-resistant breast cancer cells are resistant to DNA-damaging chemotherapy because of upregulated BARD1 and BRCA1
title Tamoxifen-resistant breast cancer cells are resistant to DNA-damaging chemotherapy because of upregulated BARD1 and BRCA1
title_full Tamoxifen-resistant breast cancer cells are resistant to DNA-damaging chemotherapy because of upregulated BARD1 and BRCA1
title_fullStr Tamoxifen-resistant breast cancer cells are resistant to DNA-damaging chemotherapy because of upregulated BARD1 and BRCA1
title_full_unstemmed Tamoxifen-resistant breast cancer cells are resistant to DNA-damaging chemotherapy because of upregulated BARD1 and BRCA1
title_short Tamoxifen-resistant breast cancer cells are resistant to DNA-damaging chemotherapy because of upregulated BARD1 and BRCA1
title_sort tamoxifen-resistant breast cancer cells are resistant to dna-damaging chemotherapy because of upregulated bard1 and brca1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5913295/
https://www.ncbi.nlm.nih.gov/pubmed/29686231
http://dx.doi.org/10.1038/s41467-018-03951-0
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