BRCA1 deficiency sensitizes breast cancer cells to bromodomain and extra-terminal domain (BET) inhibition

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 expr...

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Veröffentlicht in:Oncogene 2018-12, Vol.37 (49), p.6341-6356
Hauptverfasser: Zhang, Baoyuan, Lyu, Junfang, Liu, Yifan, Wu, Changjie, Yang, Eun Ju, Pardeshi, Lakhansing, Tan, Kaeling, Wong, Koon Ho, Chen, Qiang, Xu, Xiaoling, Deng, Chu-Xia, Shim, Joong Sup
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Sprache:eng
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Zusammenfassung: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.
ISSN:0950-9232
1476-5594
DOI:10.1038/s41388-018-0408-8