Suppression of the dynamic interaction of estrogen receptor with chromatin is critical for therapeutic ligands to repress ER-mediated transcription activities

Breast cancer (BC) is the second leading cause of cancer deaths in women with annual new cases and fatality of 1.7 million and 500,000 respectively (1). Estrogen receptorpositive (ER) BCs constitute 75% of the cases, and contribute to approximately 50% BC fatality (1). ERα plays critical roles in BC progression in part via transactivating Myc, cyclin D1, vascular endothelial growth factor, and other important oncogenic factors (2,3). Targeting ERα remains the standard of care in ER BCs; endocrine therapy (ET) is likely the most successful targeted cancer therapies. Adjuvant tamoxifen decreases mortality and recurrence by 31% and 50% respectively (4,5). The current toolbox of ET includes estrogen biosynthesis inhibitors (aromatase inhibitors, AIs) and therapeutic ligands; the latter consists of selective estrogen modulators (SERMs, like tamoxifen) and fulvestrant, a selective estrogen down-regulator (SERD). Although ET is clearly beneficial and with multiple options, ER BCs remains a major cause of BC mortality because of resistance. While resistance to ET (ETR) is mediated by complex mechanisms, persistent ER signaling under ET is a major attributor to the resistance; loss of ERα was reported in 17–28% of relapse BCs (6-8). The contributions of ERα in relapse BCs underlies multiple rounds of ET using alternative endocrine treatment. For instance, approximately 20% of relapse ER BCs following tamoxifen treatment are sensitive to AI and fulvestrant (9,10) and approximately 40% of recurrent ER BCs have mutations in ERα (11). Collectively, evidence supports an important role of persistent ERα function in ETR development. The above situation also outlines a clear need to more effectively target ERα. Tamoxifen possesses partial agonist activities. In comparison, fulvestrant is a pure antagonist and thus a more potent antiestrogen, which is attributable to its action of inducing ERα degradation. However, the clinical application of fulvestrant is limited because of its poor solubility and intramuscular route of administration (12,13). This status underlies the current interest in developing new SERDs with improved pharmacokinetic properties for oral administration. Several of these SERDs have been developed and entered clinical trials, including GDC-0810 (multicenter phase Ia/ IIa: NCT01823835), AZD9496 (phase I: NCT02248090; an open-label randomized multicenter trial: NCT03236974), RAD1901 (Elacetrant; phase III: NCT03778931; EudraCT 2018-002990-24), GDC-0927 (NCT02316509), and others. To develop effective antiestrogen ligands, a deep understanding of the mechanisms utilized by the current therapeutic ligands will provide a framework to guide this effort. ERα has been extensively investigated (the number of articles listed in PubMed under “estrogen receptor alpha”: n=20,816) following the cloning of human ERα from MCF7 cells in 1986 (14). ERα is a member of the nuclear receptor superfamily; it consists of 6 domains A-F with domain C Editorial Commentary