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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Bibliographic Details
Published in:Oncogene 2018-12, Vol.37 (49), p.6341-6356
Main Authors: 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
Format: Article
Language:English
Subjects:
13/89
38/91
631/154/1435
631/67/1347
64/60
96/2
96/47
Apoptosis
Biochemistry
BRCA1 protein
Breast cancer
Cancer cells
Cancer genetics
Care and treatment
Cell Biology
Data processing
Deoxyribonucleic acid
Development and progression
DNA
Epigenetic inheritance
Epigenetics
Gene expression
Gene mutation
Gene silencing
Genes
Genetic aspects
Health aspects
Human Genetics
Information management
Internal Medicine
Lethality
Medicine
Medicine & Public Health
Myc protein
Oncology
Ovarian cancer
Oxidative stress
Thioredoxin
Thioredoxins
Transcription (Genetics)
Tumor suppressor genes
Tumors
Xenografts
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Summary: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