Interactions between Pro-inflammatory Cytokines and Estrogen Receptors in Endometrial Cancer

Abstract

Endometrial cancer (EC) is a hormone-driven malignancy in which estrogen receptor (ER) signaling plays a central role. Meanwhile, chronic inflammation, particularly mediated by pro-inflammatory cytokines such as interleukin-6 (IL-6) and interleukin-17 (IL-17), has emerged as a key contributor to endometrial cancer progression. This review examines the interplay between IL-6, IL-17, and estrogen receptors (ERα and ERβ) in endometrial cancer cells, highlighting how these cytokines regulate ER expression and function through multiple signaling pathways, including the Janus kinase/signal transducer and activator of transcription (JAK/STAT), nuclear factor-κB (NF-κB), and mitogen-activated protein kinase (MAPK) pathways. IL-6 and IL-17 have been shown to upregulate ERα and suppress ERβ, thereby enhancing estrogen-mediated tumor proliferation and potentially contributing to hormonal therapy resistance. Moreover, evidence suggests a bidirectional feedback loop in which estrogen signaling further amplifies cytokine production, creating a self-sustaining inflammatory environment that promotes tumor progression. Understanding this cytokine–ER crosstalk provides novel insights into endometrial cancer pathogenesis and reveals potential therapeutic targets. Strategies that combine endocrine therapy with anti-inflammatory agents or cytokine pathway inhibitors may help overcome resistance and improve clinical outcomes in selected patients. Further mechanistic studies and clinical trials are needed to validate the prognostic and therapeutic relevance of IL-6 and IL-17 in hormone-responsive endometrial cancer.