Garcia-Carpizo, VeronicaRuiz-Llorente, SergioSarmentero, JacintoGonzález-Corpas, AnaBarrero, Maria J2026-02-272026-02-272019-03Mol Cancer Res . 2019 Mar;17(3):720-730.https://hdl.handle.net/20.500.12105/27279The authors would like to thank the Spanish State Public Employment Service (SEPE) for support during the preparation of this manuscript. We thank the Flow Cytometry andGenomics Units, O. Grana and the Bioinformatics Unit at the CNIO for assistance in the bioinformatics analysis, andM. Serrano and M. Malumbres for constructive discussions. This work was funded by Eli Lilly and CompanyInhibitors that prevent the binding of bromodomains to acetylated histones hold therapeutic potential. However, the effects of targeting most of the 60 different bromodomains found in the human proteome remain unexplored. Here, we investigate the molecular mechanisms responsible for the antiproliferative properties of CREBBP/EP300 bromodomain inhibition in ER-negative breast cancer cell lines. We show using genetic and chemical approaches that CREBBP/EP300 bromodomains are critical to support the proliferation of the triple-negative breast cancer cell line MDA-MB-453. Analysis of the transcriptional pathways affected by CREBBP/EP300 bromodomain inhibitors reveals that the expression of genes associated with super-enhancers is downregulated, which in turn are occupied by very high levels of androgen receptor (AR) in MDA-MB-453 cells. Treatment of MDA-MB-453 with CREBBP/EP300 bromodomain inhibitors downregulates the expression of an AR-dependent signature distinctive of breast cancer tumors that express AR and causes a decrease in H3K27ac levels at AR-binding sites. In accordance, in prostate cancer cell lines that express AR CREBBP/EP300 bromodomain inhibitors downregulate the expression of genes bound by AR and associated with super-enhancers. In summary, we report that triple-negative breast cancer cell lines that express AR are particularly sensitive to CREBBP/EP300 bromodomain inhibitors and consequently these inhibitors hold potential to treat this type of cancer. IMPLICATIONS: AR-dependent cancer cell lines are sensitive to CREBBP/EP300 bromodomain inhibitors.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/OPTIMIZATIONCREB-BINDING-PROTEINSMALL-MOLECULE INHIBITORANDROGEN RECEPTORCBP/P300 BROMODOMAINDISCOVERYP300IDENTIFICATIONTRANSCRIPTIONTARGETSOPTIMIZATIONAttribution-NonCommercial-NoDerivatives 4.0 International30606771173720-730Mol Cancer Resopen access