Estrogen receptors (ERs) and their ligands (estrogens) are important regulators of cell type-specific patterns of gene expression that control a diverse array of physiological processes in many tissues. Cellular signaling by estrogens occurs through at least two distinct molecular pathways involving different enhancer DNA elements: (1) direct binding of liganded ERs to estrogen response elements (EREs) (the """"""""ER/ERE pathway"""""""") and (2) indirect association of liganded ERs with AP-1-responsive elements via heterodimers of Fos and Jun (the """"""""ER/AP-1 pathway""""""""). Both pathways require a host of coregulatory proteins (e.g. coactivators and corepressors), although the distinct coactivator requirements for each pathway have not been defined. The long-term objective of these studies is to achieve a better understanding of the molecular mechanisms of ligand-regulated transcription by ERs and their associated coregulators in the chromatin environment of the nucleus. Although great strides have been made in understanding some of the molecular details of estrogen signaling, our understanding of the ER/AP-1 pathway, the role of chromatin remodeling complexes, and the mechanisms of cell type- and ligand-specific responses is limited. Our broad hypothesis is that transcriptional outcomes in estrogen signaling pathways are ultimately determined by a number of receptor and non-receptor factors, including the ER isoform (ERa vs. ERb), cell type-specific repertoire of coregulators, type of enhancer elements, nature of the ligand, and cross-talk with other signaling pathways. In this proposal, we outline a series of experiments using biochemical, cell-based, and genomic approaches that will test this hypothesis. Specifically, we will: (1) determine the molecular mechanisms underlying cell type-specific transcriptional activation in the ER/AP-1 pathway by estrogens and selective ER modulator (SERM) drugs, (2) examine the role of chromatin remodeling and the requirement for specific chromatin remodeling complexes in ER-dependent transcription, and (3) analyze coactivator recruitment and chromatin remodeling at ER-regulated promoters on a genome-wide basis. Collectively, our studies will provide new insights into the molecular mechanisms of estrogen signaling and the cell type specific molecular pharmacology of SERMs, which have implications for understanding and treating hormone-regulated cancers.
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