Abstract BS1-2: Epigenetic targets in breast cancer

Abstract

Abstract Epigenetic regulators are emerging therapeutic targets in various human cancer types including breast cancer. Histone modification (e.g., methylation and acetylation) regulates chromatin structure and transcription, and abnormalities in this process lead to perturbed development and differentiation. Similarly, DNA methylation patterns are commonly perturbed in tumors and this can increase genetic instability and also cellular heterogeneity within tumors. The demonstration of frequent somatic mutations in histones and epigenetic regulators factors in a wide range of human cancer types underscores the importance of epigenetic regulation in tumorigenesis. In breast cancer, genes encoding transcriptional regulators (e.g., FOXA1, GATA3) are among the most frequently mutated genes, suggesting a key role for perturbed epigenetic programs in tumorigenesis. Epigenetic regulators are broadly categorized into writers – enzymes that catalyze the placement of modifications in histones or DNA such as histone and DNA methyltransferases, erasers – enzymes that remove histone or DNA modifications including histone and DNA demethylases, and readers – proteins that recognize a specific histone or DNA modification to help concentrate an enzymatic or structural protein complex. BET bromodomain family of chromatin regulators (e.g., BRD4) recognize acetylated histones and play a key role in the assembly of active transcription complexes. Targeting of these proteins by BET bromodomain inhibitors (BBDIs) have been shown to inhibit the growth of several cancer types and they appear promising novel therapeutic agents in breast cancer as well. However, a significant fraction of breast cancer cells is not sensitive to BBDIs and even some of the initial responsive ones relatively quickly acquire resistance due to activation of anti-apoptotic pathways and bromodomain-independent recruitment of BRD4 to the chromatin. Thus, inhibitors of BET bromodomain proteins alone or in combination with other compounds provide a promising novel therapeutic strategy for the treatment of breast tumors. Citation Format: Polyak K. Epigenetic targets in breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr BS1-2.