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 and Qiang Liu ()
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Yinghua Zhu: Sun Yat-Sen University
Yujie Liu: Sun Yat-Sen University
Chao Zhang: Sun Yat-Sen University
Junjun Chu: Sun Yat-Sen University
Yanqing Wu: Sun Yat-Sen University
Yudong Li: Sun Yat-Sen University
Jieqiong Liu: Sun Yat-Sen University
Qian Li: Sun Yat-Sen University
Shunying Li: Sun Yat-Sen University
Qianfeng Shi: Sun Yat-Sen University
Liang Jin: Sun Yat-Sen University
Jianli Zhao: Sun Yat-Sen University
Dong Yin: Sun Yat-Sen University
Sol Efroni: Bar-Ilan University
Fengxi Su: Sun Yat-Sen University
Herui Yao: Sun Yat-Sen University
Erwei Song: Sun Yat-Sen University
Qiang Liu: Sun Yat-Sen University

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03951-0

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