Pharmacologic\nInduction of ERα SUMOylation Disrupts\nIts Chromatin Binding

Estrogen receptor α (ERα)-positive breast\ncancer patients\nare typically treated with ERα inhibitors, including selective\nestrogen receptor modulators (SERMs) and selective estrogen receptor\ndegraders (SERDs). However, the distinct pharmacological properties\nof various ERα inhibitors remain incompletely understood. In\nthis study, we employed formaldehyde cross-linking followed by ERα\nimmunoprecipitation and mass spectrometry to reveal that fulvestrant,\nthe first FDA-approved SERD, induces the interaction between ERα\nand SUMO E3 ligases PIAS1 and PIAS2. Biochemical and genomic assays\nconfirmed that fulvestrant induces SUMOylation of ERα, which\ninhibits ERα′s binding to chromatin DNA. In addition,\nraloxifene (a SERM) and elacestrant (the first FDA-approved oral SERD)\nwere identified as compounds that similarly induce ERα SUMOylation\nand inhibit its chromatin interaction. Our findings reveal a mechanism\nby which select ERα inhibitors disrupt ERα function through\nSUMOylation, offering insights for the development of next-generation\nERα-targeted therapies.