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

Oncogene volume 37, pages 6341–6356 (2018)Cite this article

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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.

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Acknowledgements

We thank to the members of the Genomics and Bioinformatics Core of FHS at UM for experimental and technical supports for the RNA-sequencing and data analyses and to Jacky Chan and William Pang from ICTO at UM for supporting the High Performance Computing cluster. We are also grateful to the members of FHS Animal Facility at UM for arranging and maintaining experimental animals for this study. This work was supported by the Multi-Year Research Grant of the University of Macau (MYRG2015-00181-FHS and MYRG2017-00176-FHS to J.S.S) and the Science and Technology Development Fund (FDCT) of Macau SAR (FDCT/024/2015/A1 to J.S.S).

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  1. Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, 999078, Macau, SAR, China

    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

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Zhang, B., Lyu, J., Liu, Y. et al. BRCA1 deficiency sensitizes breast cancer cells to bromodomain and extra-terminal domain (BET) inhibition. Oncogene 37, 6341–6356 (2018). https://doi.org/10.1038/s41388-018-0408-8

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