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SGK3 sustains ERα signaling and drives acquired aromatase inhibitor resistance through maintaining endoplasmic reticulum homeostasis

Significance Acquired aromatase inhibitor (AI) resistance is a major clinical issue in the treatment of estrogen receptor alpha (ERα)-positive breast cancer. Most AI-resistant breast tumors still express ERα and rely on its signaling for growth. The current study shows that serum- and glucocorticoid-inducible kinase 3 (SGK3), a kinase transcriptionally regulated by ERα in breast cancer, sustains ERα signaling and drives the acquired AI resistance by protecting against endoplasmic reticulum (EnR) stress-induced ERα downregulation and cell death through preserving sarcoplasmic/EnR calcium ATPase 2b (SERCA2b) function. Our study reveals regulation of ERα expression mediated by the EnR stress response and highlights SGK3 inhibition as a potential effective treatment of acquired AI-resistant breast cancer. Many estrogen receptor alpha (ERα)-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 ERα in breast cancer, sustains ERα 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 ERα expression through the protein kinase RNA-like EnR kinase (PERK) arm, and SGK3 retains ERα expression and signaling by preventing excessive EnR stress. Our study reveals regulation of ERα expression mediated by the EnR stress response and the feed-forward regulation between SGK3 and ERα in breast cancer. Given SGK3 inhibition reduces AI-resistant cell survival by eliciting excessive EnR stress and also depletes ERα expression/function, we propose SGK3 inhibition as a potential effective treatment of acquired AI-resistant breast cancer.