Abstract 4669: Pharmacologic inhibition of CBP/p300 suppresses estrogen-induced gene expression and proliferation in ER+ luminal breast cancer cells
Authors: Waddell Aaron Richard , Mahmud Iqbal , Huo Zhiguang , Liao Daiqing 
Published: September 2020

Abstract
Luminal breast cancer, defined by the expression of the estrogen receptor alpha (ERα), comprises nearly two thirds of all breast cancer cases and most patients with breast cancer die of this subtype. ERα is a steroid nuclear receptor that functions as a transcription factor to upregulate genes such as MYC that are involved in cell cycle progression. Antagonists of ERα are the standard of care treatment for ER+ luminal breast cancer, but resistance to these antagonists in advanced patients is a major clinical issue. Therefore, there is an unmet medical need to develop more effective therapies for treating ER+ breast cancer. CBP/p300 are two paralogous acetyltransferases that catalyze histone acetylation at enhancers and promoters to activate gene expression. They serve as transcriptional co-activators for several oncogenic signaling pathways, including the pro-growth androgen and estrogen signaling pathways in cancer. Due to their emerging role in promoting tumor growth, the oncogenic functions of CBP/p300 and means of their pharmacologic inhibition are under intense investigation for developing potential therapeutics for cancer treatment. CBP/p300's acetyltransferase (HAT) domain and their bromodomain represent tractable drug targets and potent and specific small molecule inhibitors have been developed for both. However, the pharmacologic effects and anticancer efficacy of these compounds in breast cancer remain largely unexplored. Previous research shows that CBP/p300 serve as co-activators for ERα and are responsible for catalyzing Histone 3, lysine 18 and 27 acetylation (H3K18ac and H3K27ac) at ERα target genes. We hypothesize that CBP/p300 are critical for ERα function in driving oncogene expression and their pharmacologic inhibition will block ERα-mediated gene expression underpinning the tumor growth of luminal breast cancer. In support of our hypothesis, we report that small molecule inhibitors of the CBP/p300 HAT domain and bromodomain strongly inhibit estrogen- induced MYC expression and prevent colony formation in vitro of a panel of ER+ cell lines. Furthermore, inhibition of CBP/p300 also downregulates ERα activity in a luciferase assay using a construct driven by the conical ERα-binding DNA sequence. H3K27ac ChIP-seq data in the ER+ luminal breast cancer MCF-7 cells indicate that pharmacologic inhibition of CBP/p300 catalytic function blocks specific enhancer function. Our study suggests pharmacologically targeting CBP/p300 may be an effective strategy for treating luminal breast cancer. (Supported by James and Esther King Biomedical Research Program, and Bankhead-Coley Cancer Research Program, Florida Department of Health)
Citation Format: Aaron Richard Waddell, Iqbal Mahmud, Zhiguang Huo, Daiqing Liao. Pharmacologic inhibition of CBP/p300 suppresses estrogen-induced gene expression and proliferation in ER+ luminal breast cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4669.