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

Yinghua Zhu; Yujie Liu; Chao Zhang; Junjun Chu; Yanqing Wu; Yudong Li; Jieqiong Liu; Qian Li; Shunying Li; Qianfeng Shi; Liang Jin; Jianli Zhao; Dong Yin; Sol Efroni; Fengxi Su; Herui Yao; Erwei Song; Qiang Liu

doi:10.1038/s41467-018-03951-0

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

Yinghua Zhu, Yujie Liu, Chao Zhang, Junjun Chu, Yanqing Wu, Yudong Li, Jieqiong Liu, Qian Li, Shunying Li, Qianfeng Shi, Liang Jin, Jianli Zhao, Dong Yin, Sol Efroni, Fengxi Su, Herui Yao, Erwei Song, Qiang Liu

The Mina and Everard Goodman Faculty of Life Sciences

Sun Yat-Sen University

Research output: Contribution to journal › Article › peer-review

99 Scopus citations

Abstract

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.

Original language	English
Article number	1595
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-03951-0
State	Published - 23 Apr 2018

Bibliographical note

Publisher Copyright:
© 2018 The Author(s).

Funding

This work was funded by National Key Basic Research Program of China (973 Project, 2015CB553702), Natural Science Foundation of China grants (81402505, 81630074, 81472467, 81672622, and 81702630), Guangdong International collaboration key project (2014A050503034), Guangzhou Science and Technology key projects (201804020076), Sun Yat-sen University Training Project Grants (14ykpy20). PI3K Inhibitors, BKM120 and BYL719, were kindly provided by Novartis Pharma Stein AG.

Funders	Funder number
Guangdong International collaboration key project	2014A050503034
National Natural Science Foundation of China	81472467, 81402505, 81672622, 81702630, 81630074
Sun Yat-Sen University	14ykpy20
Guangzhou Science and Technology Program key projects	201804020076
National Key Research and Development Program of China	2015CB553702

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Zhu, Y., Liu, Y., Zhang, C., Chu, J., Wu, Y., Li, Y., Liu, J., Li, Q., Li, S., Shi, Q., Jin, L., Zhao, J., Yin, D., Efroni, S., Su, F., Yao, H., Song, E., & Liu, Q. (2018). Tamoxifen-resistant breast cancer cells are resistant to DNA-damaging chemotherapy because of upregulated BARD1 and BRCA1. Nature Communications, 9(1), Article 1595. https://doi.org/10.1038/s41467-018-03951-0

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abstract = "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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AU - Efroni, Sol

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AU - Song, Erwei

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

Abstract

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