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

• DOI: 10.1038/s41467-018-03951-0
• Publication Date: 2018-04-17T09:42:15Z
• Authors: 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
• Keywords: 0301 basic medicine; Antineoplastic Agents, Hormonal; Science; Mice, Nude; Breast Neoplasms; Mice, SCID; Article; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; Mice, Inbred NOD; Animals; Humans; RNA, Small Interfering; Protein Kinase Inhibitors; Phosphoinositide-3 Kinase Inhibitors; Mice, Inbred BALB C; BRCA1 Protein; Q; Prognosis; 3. Good health; Gene Expression Regulation, Neoplastic; Drug Resistance, Neoplasm; MCF-7 Cells; Female; Proto-Oncogene Proteins c-akt; DNA Damage

AbstractTamoxifen 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.