SGK3 sustains ER[alpha] signaling and drives acquired aromatase inhibitor resistance through maintaining endoplasmic reticulum homeostasis

Many estrogen receptor alpha (ER[alpha])-positive breast cancers initially respond to aromatase inhibitors (AIs), but eventually acquire resistance. Here, we report that serum- and glucocorticoid-inducible kinase 3 (SGK3), a kinase transcriptionally regulated by ER[alpha] in breast cancer, sustains ERa signaling and drives acquired AI resistance. SGK3 is up-regulated and essential for endoplasmic reticulum (EnR) homeostasis through preserving sarcoplasmic/EnR calcium ATPase 2b (SERCA2b) function in AI-resistant cells. We have further found that EnR stress response down-regulates ER[alpha] expression through the protein kinase RNA-like EnR kinase (PERK) arm, and SGK3 retains ERa expression and signaling by preventing excessive EnR stress. Our study reveals regulation of ER[alpha] expression mediated by the EnR stress response and the feed-forward regulation between SGK3 and ER[alpha] in breast cancer. Given SGK3 inhibition reduces AI-resistant cell survival by eliciting excessive EnR stress and also depletes ER[alpha] expression/function, we propose SGK3 inhibition as a potential effective treatment of acquired AI-resistant breast cancer.