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

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 (ER) signaling in fallopian tube (FT) stromal cells plays a critical developmental role in maintaining epithelial homeostasis by promoting FTE proliferation and ciliated differentiation. Stromal ER 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 ER signaling integrates hormonal cues, inflammation, aging, and genetic susceptibility to influence early events in FT carcinogenesis. In BriefEstrogen receptor 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. O_FIG O_LINKSMALLFIG WIDTH=190 HEIGHT=200 SRC="FIGDIR/small/700864v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@113b543org.highwire.dtl.DTLVardef@e1465corg.highwire.dtl.DTLVardef@1d279dcorg.highwire.dtl.DTLVardef@13e782c_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIStromal ER signaling maintains fallopian tube epithelial (FTE) cell homeostasis C_LIO_LIStromal ER promotes proliferation and ciliated differentiation of FTE cells C_LIO_LIExcess estrogen shifts this stromal niche toward tumor promotion via inflammation C_LIO_LIDifferentiation-resistant mutant FTE cells respond to stromal proliferation signals C_LI