Estradiol Promotes Tumor Progression in ERα-Low Endometrial Cancer via the GPER/SphK1 Pathway

Abstract

Endometrial cancer (EC) is the most common gynecological malignancy in postmenopausal women. Patients with low estrogen receptor alpha (ERα) expression frequently develop aggressive pathological subtypes and have poor prognosis. The role of estradiol (E2) in ERα-low EC remains poorly understood. This study investigated the tumor-promoting effects of E2 using clinical data, in vitro functional assays, and a mouse xenograft model. We found that serum E2 levels were elevated in ERα-low patients, of whom 67.7% showed high tumor expression of G protein-coupled estrogen receptor (GPER). High GPER expression correlated with increased E2 levels, enhanced sphingosine kinase 1 (SphK1) activity, and higher Ki67 proliferation index. In vitro, E2 promoted proliferation, migration, and invasion of HEC-1A cells (low ERα, high GPER). These effects were suppressed by pharmacological inhibition or siRNA knockdown of GPER or SphK1. Mechanistically, E2 activated the ERK1/2 pathway via the GPER/SphK1 axis, leading to upregulation of Cyclin D1, Cyclin E1, and MMP-9. In vivo, E2 stimulated xenograft tumor growth, an effect mitigated by inhibitors of GPER, SphK1, and ERK. Our findings demonstrate that E2 drives progression of ERα-low endometrial cancer through the GPER/SphK1 signaling pathway, revealing potential therapeutic targets for this high-risk subgroup.