The AF-2 cofactor binding region is key for the selective SUMOylation of estrogen receptor alpha by antiestrogens

Antiestrogens are used to treat all stages of Estrogen Receptor (ER)-positive breast Cancer. Selective Estrogen Receptor Modulators (SERMs) such as tamoxifen have tissue-specific partial agonist activity, while Selective Estrogen Receptor Downregulators (SERDs) such as fulvestrant (ICI182,780) display a more complete antiestrogenic profile. We have previously observed that fulvestrant-induced ERα SUMOylation contributes to transcriptional suppression, but whether this effect is seen with other antiestrogens and is specific to ERα is unclear. Here we show that several antiestrogens induce SUMOylation of ERα, but not ERβ, at different levels. Swapping domains between ERα and ERβ indicates that the ERα identity of the Ligand Binding Domain (LBD) helices 3 and 4 (H3-H4 region), which contribute to the static part of the Activation Function-2 (AF-2) cofactor binding groove, is sufficient to confer fulvestrant-induced SUMOylation to ERβ. This region does not contain Lysine residues unique to ERα, suggesting that ERα-specific residues in H3-H4 determine the capacity of the antiestrogen-bound ERα LBD to recruit the SUMOylation machinery. We also show that the SUMO E3 ligase Protein Inhibitor of Activated STAT 1 (PIAS1) increases SUMOylation of ERα, and of ERβ containing the H3-H4 region of ERα, but not of ERβ. Together, these results shed new LIGHT on the molecular basis for the differential capacity of SERMs and SERDs to suppress transcription by ERα.

Breast cancer; Estrogen Receptors; Protein Inhibitor of Activated STAT 1 (PIAS1); SUMOylation; Selective Estrogen Receptor Downregulators (SERDs).