ORF48-02 - The Structural Basis of Ligand-Specific Estrogen Receptor Alpha Transcriptional Rewiring

Breast cancer is the second leading cause of cancer-related death in women in the United States. Over 70% of breast cancer cases are driven by estrogen receptor alpha (ERα), a steroid hormone receptor that works as a master transcriptional regulator controlling the expression of over 9,000 genes. Many antiestrogens have been designed to outcompete the endogenous ligand, 17β-estradiol, and favor alternate conformations of ERα that result in distinct transcriptional complexes. Despite years of research, the allosteric mechanisms that govern antiestrogenic actions are not fully understood. X-ray co-crystal structures of ERα ligand binding domain (LBD) show nearly identical conformational ensembles, likely due to crystal packing constraints. Since these ligands can uniquely impact transcriptional programs within breast cancer cells, which depend on the formation of ligand-specific ERα complexes, we hypothesize that ligand-specific allosteric networks initiated at the LBD propagate to other domains of the receptor to form distinct quaternary structures. Through a combination of computational, biophysical, and cell-based approaches, we have begun to map these allosteric mechanisms from the ligand binding pocket to the full-length receptor. With an improved understanding of interdomain communication, we can better program ERα to engage more effective anti-cancer efficacies to improve patient survival and quality of life.