ORF48-05 - Ligand and Context Specific Estrogen Receptor Interactomes

Estrogen receptor alpha (ERα) is a ligand-dependent nuclear hormone receptor responsible for activating proliferative and metastatic transcriptomes in approximately 70% of breast cancers (BC). Mechanistically, estrogen binding favors ERα conformational ensembles that lead to the formation of transcriptional coregulator complexes. Current treatment of ERα+ BC involves treatment with endocrine therapies (ET) many of which are competitive allosteric regulators that alter transcriptional complex assemblies. The Selective Estrogen Receptor Modulator (SERM) tamoxifen (active metabolite: 4OHT) is the standard-of-care first line ET in pre-menopausal women with ERα+ breast cancer, boasting a 96% 5-year survival rate in adjuvant treatment regimens. However, 4OHT is known to act as a weak estrogen in the uterus, leading to 1.5% of BC patients to be diagnosed with endometrial cancer, with this risk increasing over prolonged treatment periods.
Despite years of research, it is unclear what is driving therapeutic outcomes and tissue-specific activities of tamoxifen. However, tissue-specific transcriptomic activities may arise due to the unique milieu of coregulators present in estrogen responsive tissues. Coregulators harbor diverse protein functions with many acting as epigenetic regulators to dictate transcriptional reprogramming. As such, tissue-specific coregulator assemblies may explain tamoxifen breast antagonism versus endometrial partial agonism. Therefore, we hypothesize that ET pharmacology arises from the recruitment of discrete ligand- and context- specific ERα- coregulator complexes.
Preliminary data from a proximity-labeling mass spectrometry proteomic approach in the Ishikawa cells reveals nuclear coregulators that associate with endogenous estrogen (E2) and 4OHT bound ERα in the endometrial context. Overlap between the agonist E2 and antagonist 4OHT signifies protein-protein interactions that may be responsible for 4OHT partial agonism in the endometrium. This aim will uncover therapeutic modes of tamoxifen transcriptional regulation by revealing pro- and anti- oncogenic protein-protein interactions responsible for clinical outcomes. This knowledge will be leveraged for informed personalized prognostics or combination therapy to decrease uterotrophism.