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Nat Commun. 2018 Apr 23;9(1):1595. doi: 10.1038/s41467-018-03951-0.

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

Zhu Y1,2,3, Liu Y1,2, Zhang C1,2, Chu J1,3, Wu Y1,2, Li Y1,2, Liu J1,2, Li Q1,2, Li S1,2, Shi Q1,2, Jin L1,2, Zhao J1,2, Yin D1,3, Efroni S4, Su F1,2, Yao H1,2, Song E1,2,3, Liu Q5,6.

Author information

1
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 510120, Guangzhou, China.
2
Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 510120, Guangzhou, China.
3
Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 510120, Guangzhou, China.
4
Faculty of Life Sciences, Bar-Ilan University, 52900, Ramat Gan, Israel.
5
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 510120, Guangzhou, China. victorlq@hotmail.com.
6
Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 510120, Guangzhou, China. victorlq@hotmail.com.

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.

PMID:
29686231
PMCID:
PMC5913295
DOI:
10.1038/s41467-018-03951-0
[Indexed for MEDLINE]
Free PMC Article

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