Targeting the ERα DBD-LBD Interface with Mitoxantrone Disrupts Receptor Function through Proteasomal Degradation.

ABSTRACT: The estrogen receptor (ER or ERα) remains the primary therapeutic target for luminal breast cancer, with current treatments centered on competitive antagonists, receptor downregulators, and aromatase inhibitors. Despite these options, resistance frequently emerges, highlighting the need for alternative targeting strategies. We discovered a novel mechanism of ER inhibition that targets the previously unexplored interface between the DNA-binding domain (DBD) and ligand-binding domain (LBD) of the receptor. Through computational screening and functional assays, we identified mitoxantrone (MTO), an FDA-approved topoisomerase II inhibitor, as a specific ligand for this DBD-LBD interface. Comprehensive biophysical, biochemical, and cellular analyses demonstrate that MTO binding induces distinct

SUBMITTER: Wang H 

PROVIDER: S-EPMC12496009 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature