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.