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.

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

“…Most recently, Bago et al reported that SGK3 counteracts the inhibition of PI3K/Akt signaling and stimulates tumor growth (12). SGK3 is amplified and hyperactivated in breast cancer (13), and its expression is regulated by ERα and positively correlates with ERα levels in breast tumors (14,15). Here, we report a mechanism with which SGK3 sustains ERα signaling and drives acquired AI resistance by maintaining EnR homeostasis through preserving SERCA2b function in breast cancer.…”

“…After AI exposure, most estrogen-dependent cancer cells stop proliferation and go through apoptosis and/or autophagy, but some cancer cells gain estrogen hypersensitivity by ERα mutations or the cross-talk of ERα with growth factor signaling pathways, so that cancer cells can survive and proliferate at low levels of estrogen. Previously, we and others have reported that SGK3 is an ERα direct target, and SGK3 levels positively correlate with ERα levels in breast tumors (14,15). SGK3 can enhance ERα transactivation through phosphorylation of coactivator Flightless-I (25).…”

“…Previously, we reported that SGK3 is transcriptionally regulated by estrogens and androgens (15,17). We examined the effect of selective ER degrader ICI182,780 (fulvestrant) and anti-androgen enzalutamide on SGK3 expression in AI-resistant cells.…”

“…SGK3 can be transcriptionally up-regulated by both ERα and AR, but AR regulation of SGK3 expression requires the presence of ERα (15,17). Because AI blocks the conversion of androgens to estrogens, the levels of intratumoral androgens are elevated after treatment with AIs (34), which might up-regulate SGK3 and thus promote AI resistance.…”

Coordinated Regulation of Serum- and Glucocorticoid-inducible Kinase 3 by a C-terminal Hydrophobic Motif and Hsp90-Cdc37 Chaperone Complex

“…SGK3 is amplified and acts as an oncogene in hepatocellular carcinoma (6). Several studies, including our own, have shown that SGK3 is up-regulated in breast cancer, especially in estrogen receptor (ER)-positive breast cancer (7)(8)(9)(10), and promotes estrogen-mediated cell survival (8,11). Furthermore, Slagsvold et al (12) reported that SGK3 attenuates the degradation of chemokine receptor CXCR4 and promotes breast cancer metastasis.…”