CREBBP/EP300 Bromodomain Inhibition Affects the Proliferation of AR-Positive Breast Cancer Cell Lines

• Published in: Molecular cancer research Vol. 17; no. 3; pp. 720 - 730
• Main Authors: Garcia-Carpizo, Veronica, Ruiz-Llorente, Sergio, Sarmentero, Jacinto, González-Corpas, Ana, Barrero, Maria J
• Format: Journal Article
• Language: English
• Published: United States 01.03.2019
• Subjects: Androgens - pharmacology; Azepines - pharmacology; Benzimidazoles - pharmacology; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Proliferation - physiology; CREB-Binding Protein - antagonists & inhibitors; Down-Regulation - drug effects; E1A-Associated p300 Protein - antagonists & inhibitors; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; Isoxazoles - pharmacology; Protein Domains; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Triazoles - pharmacology
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.mcr-18-0719

Inhibitors 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.