Stromal estrogen signaling regulates fallopian tube homeostasis and cancer initiation via inflammatory pathways

Summary Lifetime estrogen exposure is a major risk factor for ovarian cancer, which can originate from fallopian tube epithelial (FTE) cells. Here we report that estrogen receptor α (ERα) signaling in fallopian tube (FT) stromal cells plays a critical developmental role in maintaining epithelial homeostasis by promoting FTE proliferation and ciliated differentiation. Stromal ERα regulates expression of inflammatory cytokines, growth factors, and extracellular matrix components, creating a differentiation-supportive, tumor-suppressive niche that coordinates epithelial regeneration during hormonal cycles. Excessive or prolonged estrogen exposure, however, shifts this niche toward a tumor-promoting state by inducing inflammation and activating stemness-associated pathways, including JAK/STAT, in FTE cells. This effect is exacerbated in genetically altered FTE cells lacking key tumor suppressors, which resist differentiation while remaining responsive to stromal proliferation signals. These findings reveal how stromal ERα signaling integrates hormonal cues, inflammation, aging, and genetic susceptibility to influence early events in FT carcinogenesis. In Brief Estrogen receptor α signaling in fallopian tube stromal cells maintains epithelial homeostasis by promoting proliferation and ciliated differentiation. Excessive estrogen shifts this niche toward inflammation and stemness, cooperating with genetic susceptibility to drive early fallopian tube carcinogenesis. Abstract Figure Highlights Stromal ERα signaling maintains fallopian tube epithelial (FTE) cell homeostasis Stromal ERα promotes proliferation and ciliated differentiation of FTE cells Excess estrogen shifts this stromal niche toward tumor promotion via inflammation Differentiation-resistant mutant FTE cells respond to stromal proliferation signals