Approximately 70% of breast cancers are estrogen receptor positive, of which 40% have ER mutations. Some of these mutations occur in the three intrinsically disordered regions (IDRs) of estrogen receptor-α (ERα). It is not fully understood how these mutations affect the function of ERα, however they have been suggested to affect DNA and ligand binding, transcriptional activation and dimerization. In this study, we used mammalian one-hybrid (M1H) assays to determine the effect of deletions and mutations in the IDRs on the activation of ERα. We found that deletions in the N- and C-terminal IDRs and 7/11 patient mutations tested decreased the transcriptional activation of ERα in the presence of 17β-estradiol (E2). Interestingly, a 23x glycine-serine replacement of the hinge IDR replacement resulted in a 7-fold increase in activation. Our results show that IDRs are important for full transcriptional activation and regulation of ERα. / 2025-06-23T00:00:00Z