Abstract

Although hormones are well-established contributors to prostate and breast cancers, their role in gastric cancer remains poorly understood. Clinical observations have revealed a strong correlation between female hormone levels and the risk of developing gastric cancer, particularly in women with high estrogen levels during pregnancy or lactation, who tend to have worse prognoses. However, the precise mechanisms by which estrogen (E2) and its receptors drive gastric cancer progression are not fully elucidated. Our studies demonstrates that estrogen receptor ERβ, but not ERα, promotes the proliferation of E2-responsive gastric cancer cells. Genetic ablation of ERβ significantly suppresses the growth of subcutaneous tumors in mice. RNA-seq analysis identified PIK3R2, a PI3K regulatory subunit, as the most significantly E2-regulated gene, and luciferase reporter assays further validated PIK3R2 as a direct transcriptional target of ERβ. Clinically, PIK3R2 is significantly upregulated in gastric cancer, with elevated expression levels correlating with poor prognosis specifically in female patients, whereas no significant prognostic association was observed in male patients. These findings underscore the critical role of the ERβ/PIK3R2 signaling axis in estrogen-related gastric cancer, providing a potential therapeutic strategy for this subset of patients.