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 ER alpha signaling and drives acquired AI resistance. SGK3 is up-regulated and essential for endoplasmic reticulum (EnR) homeostasis through preserving sarcoplasm ic/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 ER alpha 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.