When Estrogen Signaling Refuses to Die: Receptor Rewiring, Compartmentalization, and Endocrine Plasticity in Gynecological Cancers

Abstract

Although estrogen signaling plays an important role in gynecological cancers, its function is highly context-dependent and often contradictory. Estrogen receptors have been associated with both tumor-promoting and tumor-suppressive effects depending on the tumor type, disease stage, and cellular environment. This review summarizes the current evidence on estrogen receptor signaling in cervical, ovarian, and endometrial cancers, focusing on receptor subtype balance, isoform diversity, cellular and subcellular localization, and epigenetic regulation. Rather than a static marker, estrogen receptor expression is revealed as a dynamic and plastic signaling network. In cervical cancer, estrogen signaling persists despite the loss of epithelial estrogen receptor α (ERα) through stromal signaling, alternative ERα isoforms, ERβ, and non-classical receptors such as G protein-coupled estrogen receptor 1 (GPER1). In ovarian cancer, epigenetic silencing of ERβ and ERα predominance drives oncogenic signaling while also creating specific biological vulnerabilities. In endometrial cancer, estrogen signaling shifts from hormone-dependent initiation to progressive oncogenic autonomy through receptor rewiring and non-genomic pathways. By integrating these mechanisms, this review highlights estrogen receptor plasticity as a unifying concept across gynecological malignancies and outlines key knowledge gaps that are relevant for future endocrine strategies.