Induced Estrogen Receptor SUMOylation drives SERD activity

The ligand dependent transcription factor estrogen receptor ERa is a key driver of and important drug target in breast cancer. Patients with advanced disease are typically treated with selective ERa degraders (SERDs), whose therapeutic activity is commonly attributed to induced ERa protein degradation. Yet the exact mechanism and relevance of degradation for clinical efficacy remain unclear. We show that SERDs directly induce ERa SUMOylation, thereby triggering degradation via SUMO-targeted ubiquitin ligases (STUbLs). Inactivation of STUbLs prevents ERa degradation and counterintuitively further sensitizes breast cancer cells to SERDs, rather than conferring resistance. SERD efficacy is independent of ERa degradation, challenging the degradation-centric model of SERD action. Instead, SUMOylation recruits transcriptional co-repressors, turning SUMOylated ERa into a dominant-negative repressor. Thus, SUMOylation rather than degradation is the direct consequence and driver of SERD activity. Our findings position SUMO-inducing drugs as a hitherto underappreciated yet clinically validated therapeutic modality with broad applicability.