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BRCA1 deficiency sensitizes breast cancer cells to bromodomain and extra-terminal domain (BET) inhibition
Baoyuan Zhang; Junfang Lyu; Yifan Liu; Changjie Wu; Eun Ju Yang; Lakhansing Pardeshi; Kaeling Tan; Koon Ho Wong; Qiang Chen; Xiaoling Xu; Chu-Xia Deng; Joong Sup Shim
2018-07-24
Source PublicationOncogene
ISSN0950-9232
Issue37Pages:6341–6356
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

DOIhttps://doi.org/10.1038/s41388-018-0408-8
Indexed BySCI
Language英语
WOS Research AreaBiochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity
WOS SubjectBiochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity
WOS IDWOS:000452384400005
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Cited Times [WOS]:1   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Corresponding AuthorJoong Sup Shim
AffiliationFaculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, 999078 Macau, SAR, China
First Author AffilicationFaculty of Health Sciences
Corresponding Author AffilicationFaculty of Health Sciences
Recommended Citation
GB/T 7714
Baoyuan Zhang,Junfang Lyu,Yifan Liu,et al. BRCA1 deficiency sensitizes breast cancer cells to bromodomain and extra-terminal domain (BET) inhibition[J]. Oncogene,2018(37):6341–6356.
APA Baoyuan Zhang.,Junfang Lyu.,Yifan Liu.,Changjie Wu.,Eun Ju Yang.,...&Joong Sup Shim.(2018).BRCA1 deficiency sensitizes breast cancer cells to bromodomain and extra-terminal domain (BET) inhibition.Oncogene(37),6341–6356.
MLA Baoyuan Zhang,et al."BRCA1 deficiency sensitizes breast cancer cells to bromodomain and extra-terminal domain (BET) inhibition".Oncogene .37(2018):6341–6356.
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