BRCA1 deficiency sensitizes breast cancer cells to bromodomain and extra-terminal domain (BET) inhibition. Issue 49 (6th December 2018)

• Record Type: Journal Article
• Authors: Zhang, Baoyuan; Lyu, Junfang; Liu, Yifan; Wu, Changjie; Yang, Eun; Pardeshi, Lakhansing; Tan, Kaeling; Wong, Koon; Chen, Qiang; Xu, Xiaoling; Deng, Chu-Xia; Shim, Joong
• Is Part Of: Oncogene. Volume 37:Issue 49(2018)
• Page Start: 6341
• Page End: 6356
• Publication Date: 2018-12-06
• Subjects: Oncogenes -- Periodicals; Oncogenes; Oncogenes -- Periodicals; Electronic journals; Periodicals; 616.994042
• DOI: 10.1038/s41388-018-0408-8
• Languages: English
• ISSNs: 0950-9232

Abstract

Abstract BRCA1 is a tumor suppressor frequently mutated in breast and ovarian cancer, serving it as a target for therapeutic exploitation. Here, we show that BRCA1 has a synthetic lethality interaction with an epigenetics regulator, bromodomain and extra-terminal domain (BET). BET inhibition led to gene expression changes reversing MYC-dependent transcription repression of a redox regulator, thioredoxin-interacting protein (TXNIP), via switching the promoter occupant from MYC to MondoA:MLX complex. Reversing the MYC-TXNIP axis inhibited thioredoxin activity and elevated cellular oxidative stress, causing DNA damages that are detrimental to BRCA1-deficient breast cancer cells. Tumor xenograft models and breast cancer clinical data analyses further demonstrated an in vivo synthetic lethality interaction and clinical association between BET/TXNIP and BRCA1 deficiency in the survival of breast cancer patients.