Selective targeting of BRCA1 deficient breast cancer by bromodomain and extra-terminal motif (BET) inhibitors

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	Selective targeting of BRCA1 deficient breast cancer by bromodomain and extra-terminal motif (BET) inhibitors
	Zhang, B.; Yang, E. J.; Lyu, J.; Liu, Y.; Wu, C.; Chen, Q.; Tan, K.; Wong, K. H.; Xu, X.; Deng, C.; Shim, J. S.
	2017-05-17
Source Publication	KSBMB International Conference 2017
Abstract	Breast cancer susceptible gene-1 (BRCA1) is a tumor suppressor involved in the DNA damage repair. We here employed a synthetic lethality approach to identify drugs that selectively target breast cancer carrying mutantBRCA1. We screened 2 BRCA1 isogenic cancer pairs with epigenetics compound library and found that inhibitors of bromodomain and extra-terminal motif (BETi) selectively killed mutantBRCA1 breast cancer cells. Transcriptome profiling revealed that BETi regulated genes involved in oxidative stress and DNA damage pathways. BETi treatment elevated reactive oxygen species (ROS) in the cells regardless of BRCA1 mutation status and the elevated ROS led to a significant increase in DNA damage specifically in mutantBRCA1 cells, thereby causing the cell apoptosis. These effects were partially reversed by the treatment with an antioxidant. Finally, the animal experiment showed that the tumor sizes of BETi treated mutantBRCA1 tumors decreased significantly compared to the wtBRCA1 ones. Taken together, the present study demonstrates that BETi induces cellular oxidative stress and causes DNA damage, which is detrimental to the mutantBRCA1 breast cancer cells and suggest that BET inhibitors are novel candidate drugs that selectively target BRCA1 mutant breast cancer.
Keyword	Bromodomain and extra-terminal motif BRCA1 synthetic lethality
Language	英語English
The Source to Article	PB_Publication
PUB ID	32334
Document Type	Conference paper
Collection	DEPARTMENT OF PHARMACEUTICAL SCIENCES Faculty of Health Sciences
Corresponding Author	Shim, J. S.
Recommended Citation GB/T 7714	Zhang, B.,Yang, E. J.,Lyu, J.,et al. Selective targeting of BRCA1 deficient breast cancer by bromodomain and extra-terminal motif (BET) inhibitors[C], 2017.
APA	Zhang, B.., Yang, E. J.., Lyu, J.., Liu, Y.., Wu, C.., Chen, Q.., Tan, K.., Wong, K. H.., Xu, X.., Deng, C.., & Shim, J. S. (2017). Selective targeting of BRCA1 deficient breast cancer by bromodomain and extra-terminal motif (BET) inhibitors. KSBMB International Conference 2017.

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