Abstract IA05: Understanding estrogen receptor transcription in breast cancer

Abstract

Abstract Estrogen Receptor (ER) is the defining feature of luminal breast cancers, where is functions as a transcription factor. The traditional view of ER getting recruited to promoters of target genes is too simplistic. The recent discovery of ER-DNA interaction regions from ER+ breast cancer cell lines has revealed that ER rarely associates with promoter regions of target genes and instead associates with enhancer elements significant distances from the target genes. The genomic mapping of ER binding events also revealed the enrichment of DNA motifs for Forkhead factors. The Forkhead protein FOXA1 (HNF3a) was subsequently shown to bind to ~half of the ER binding events in the genome and was required for ER to maintain interaction with DNA. We have extended on these findings to explore ER and FoxA1 functional interactions in breast cancer, with a specific focus on changes in binding dynamics that occur during endocrine resistance. To this end, we have established transcription factor mapping approaches (ChIP-seq) in primary tumor material, to investigate differential ER/FoxA1 binding that occurs during tumor progression. We have functionally explored underlying factors that contribute to altered transcription factor binding and activity. In addition, we have recently established a method for rapid unbiased discovery of protein interactomes, which we have applied to discover ER and FoxA1 associated proteins. We find unexpected interactions between ER and additional nuclear receptors in ER+ breast cancer, which appear to be important modulators of cellular growth and endocrine response. These findings help delineate the complexes that influence ER transcriptional activity and ultimately impinge on tumor progression and drug sensitivity. Citation Format: Jason S. Carroll. Understanding estrogen receptor transcription in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr IA05.