PKA-induced resistance to tamoxifen is associated with an altered orientation of ERα towards co-activator SRC-1

Abstract

Resistance to tamoxifen is observed in half of the recurrences in breast cancer, where the anti‐estrogen tamoxifen acquires agonistic properties for transactivating estrogen receptor α (ERα). In a previous study, we showed that protein kinase A (PKA)‐mediated phosphorylation of serine 305 (S305) of ERα results in resistance to tamoxifen. Now, we demonstrate that phosphorylation of S305 in ERα by PKA leads to an altered orientation between ERα and its coactivator SRC‐1, which renders the transcription complex active in the presence of tamoxifen. This altered orientation involves the C‐termini of ERα and SRC‐1, which required a prolonged AF‐1‐mediated interaction. This intermolecular reorientation as a result of PKA‐mediated phosphorylation of ERα‐S305 and tamoxifen binding provides a unique model for resistance to the anticancer drug tamoxifen.