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

  • Br J Pharmacol. 2025 Jan 28. doi: 10.1111/bph.17453.
Lie Yuan  1  2  3 ,  Yongqing Cai  4 ,  Gang Wang  1  2 ,  Xu Liu  1  5 ,  Bo Chen  1  2 ,  Duanfang Zhou  1  2 ,  Yuanli Wu  1  2 ,  Na Qu  1  2 ,  Xiaoli Li  1  2  3 ,  Weiying Zhou  1  2  3
Affiliations
  • 1. Department of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing, China.
  • 2. Chongqing Key Laboratory of Drug Metabolism, College of Pharmacy, Chongqing Medical University, Chongqing, China.
  • 3. Key Laboratory for Biochemistry and Molecular, College of Pharmacy, Chongqing Medical University, Chongqing, China.
  • 4. Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China.
  • 5. Department of Pharmacy, The Third People's Hospital of Chengdu, Sichuan, China.
PMID: 39876548 DOI: 10.1111/bph.17453
Abstract

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.

Keywords
SGK3; STAT3; ZMIZ2; cell proliferation; estrogen receptor‐positive; β‐catenin.
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