SGK3 sustains ERα signaling and drives acquired aromatase inhibitor resistance through maintaining endoplasmic reticulum homeostasis.
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.
Department of Cancer Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010.
Yuanzhong
Y
Wang
Department of Cancer Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010.
Dujin
D
Zhou
Department of Cancer Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010.
Sheryl
S
Phung
Integrative Genomics Core, Beckman Research Institute of the City of Hope, Duarte, CA 91010.
Charles
C
Warden
Department of Cancer Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010.
Rumana
R
Rashid
Department of Cancer Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010.
Nymph
N
Chan
Department of Cancer Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010; schen@coh.org.
Shiuan
S
Chen
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000235:genetics; D047072:Aromatase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D004721:Endoplasmic Reticulum / Q000502:physiology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D000099184:Serum-Glucocorticoid Regulated Kinases
D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D047628:Estrogen Receptor alpha; D017346:Protein Serine-Threonine Kinases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506487:ESR1 protein, human; C403243:SGK3 protein, human; D000099184:Serum-Glucocorticoid Regulated Kinases; C506946:ATP2A2 protein, human
SERCA2; SGK3; aromatase inhibitor; endoplasmic reticulum stress; estrogen receptor