SGK3 promotes estrogen receptor‐positive breast cancer proliferation by activating STAT3/ZMIZ2 pathway to stabilise β‐catenin

Background and Purpose Breast cancer is a leading threat to women's health, with approximately 70% of cases being estrogen receptor‐positive. SGK3 is regulated by estrogen and is positively associated with estrogen receptor expression, although its molecular role remains unclear. Experimental Approach Proteomics was used to identify SGK3's downstream targets. Tissue microarray immunofluorescence evaluated SGK3 and ZMIZ2 expression in ER+ breast cancer. Lentiviral‐mediated knockdown and overexpression of SGK3 and/or ZMIZ2 assessed their effects on cell proliferation in vitro and in vivo. Chromatin immunoprecipitation (ChIP) analyzed p‐STAT3 binding to the ZMIZ2 promoter, and Co‐immunoprecipitation (Co‐IP) examined ZMIZ2‐β‐catenin interaction. Key Results SGK3 expression was elevated in breast tumour tissues correlating with reduced patient survival. Proteomic analysis identified ZMIZ2 as a downstream target of SGK3. Overexpression of SGK3 promoted the proliferation of estrogen receptor‐positive breast cancer in MCF‐7 and T47D cells. Inhibition had the opposite effects. ZMIZ2 overexpression rescued the proliferation deficit in SGK3 knockdown cells. ZMIZ2 was found to bind and stabilises β‐catenin. Knockdown of SGK3 led to β‐catenin degradation via polyubiquitination, a process reversed by ZMIZ2 overexpression. STAT3 was identified as a downstream effector of SGK3 and its knockdown reduced cytoplasmic and nuclear p‐STAT3 and STAT3, and inhibited ZMIZ2 and β‐catenin expression. Celastrol suppressed estrogen receptor‐positive breast cancer cell proliferation by inhibiting the SGK3/STAT3/ZMIZ2/β‐catenin pathway. Conclusions and Implications SGK3 expression is associated with poorer survival rates, thus SGK3 is a potential therapeutic target. As celastrol can inhibit SGK3 expression it could be an effective therapeutic agent.