title: SGK3 is an estrogen-inducible kinase promoting estrogen-mediated survival of breast cancer cells.
abstract: Serum- and glucocorticoid-inducible kinase 3 (SGK3) is a protein kinase of the AGC family of protein kinase A, protein kinase G, and protein kinase C and functions downstream of phosphatidylinositol 3-kinase (PI3K). Recent study revealed that SGK3 plays a pivotal role in Akt/protein kinase B independent signaling downstream of oncogenic PI3KCA mutations in breast cancer. Here we report that SGK3 is an estrogen receptor (ER) transcriptional target and promotes estrogen-mediated cell survival of ER-positive breast cancer cells. Through a meta-analysis on 22 microarray studies of breast cancer in the Oncomine database, we found that the expression of SGK3 is significantly higher (5.7-fold, P < 0.001) in ER-positive tumors than in ER-negative tumors. In ER-positive breast cancer cells, SGK3 expression was found to be induced by 17β-estradiol (E(2)) in a dose- and time-dependent manner, and the induction of SGK3 mRNA by E(2) is independent of newly synthesized proteins. We identified two ERα-binding regions at the sgk3 locus through chromatin immunoprecipitation with massively parallel DNA sequencing. Promoter analysis revealed that ERα stimulates the activity of sgk3 promoters by interaction with these two ERα-binding regions on E(2) treatment. Loss-of-function analysis indicated that SGK3 is required for E(2)-mediated cell survival of MCF-7 breast carcinoma cells. Moreover, overexpression of SGK3 could partially protect MCF-7 cells against apoptosis caused by antiestrogen ICI 182,780. Together, our study defines the molecular mechanism of regulation of SGK3 by estrogen/ER and provides a new link between the PI3K pathway and ER signaling as well as a new estrogen-mediated cell survival mechanism mediated by SGK3 in breast cancer cells.
authors.affiliation: Division of Tumor Cell Biology, Beckman Research Institute of the City of Hope, 1550 East Duarte Road, Duarte, CA 91010, USA.
authors.forename: Yuanzhong
authors.initials: Y
authors.lastname: Wang
authors.forename: Dujin
authors.initials: D
authors.lastname: Zhou
authors.forename: Sheryl
authors.initials: S
authors.lastname: Phung
authors.forename: Selma
authors.initials: S
authors.lastname: Masri
authors.forename: David
authors.initials: D
authors.lastname: Smith
authors.forename: Shiuan
authors.initials: S
authors.lastname: Chen
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D001665:Binding Sites; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D000077267:Fulvestrant; D056426:Genetic Loci / Q000235:genetics; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D004958:Estradiol; D047628:Estrogen Receptor alpha; D004967:Estrogens; D000077267:Fulvestrant; D017346:Protein Serine-Threonine Kinases; C506487:ESR1 protein, human; C403243:SGK3 protein, human; D000099184:Serum-Glucocorticoid Regulated Kinases