Abstract
The ligand dependent transcription factor estrogen receptor α (ERα) is a key driver of and important drug target in breast cancer. Patients with advanced disease are typically treated with selective ERα degraders (SERDs), whose therapeutic activity is commonly attributed to induced ERα protein degradation. Yet the exact mechanism and relevance of degradation for clinical efficacy remain unclear. We show that SERDs directly induce ERα SUMOylation, thereby triggering degradation via SUMO-targeted ubiquitin ligases (STUbLs). Inactivation of STUbLs prevents ERα degradation and counterintuitively further sensitizes breast cancer cells to SERDs, rather than conferring resistance. SERD efficacy is independent of ERα degradation, challenging the degradation-centric model of SERD action. Instead, SUMOylation recruits transcriptional co-repressors, turning SUMOylated ERα 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.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 03 Jul 2026.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 7
- Comments 0