Prostaglandin (PG) F₂ is a potent bioactive lipid in the female reproductive tract and exerts its function following coupling with its heptahelical G-protein-coupled receptor (FP receptor) to initiate cell signalling and target gene transcription. In the present study we found elevated expression of fibroblast growth factor (FGF)-2, FGF receptor (FGFR1) and FP receptor, co-localised within the neoplastic epithelial cells of endometrial adenocarcinomas. We investigated a role for PGF₂-FP receptor interaction in modulating FGF2 expression and signalling using an endometrial adenocarcinoma cell line stably expressing the FP receptor to the levels detected in endometrial adenocarcinomas (FPS cells) and endometrial adenocarcinoma tissue explants. PGF₂-FP receptor activation rapidly induced FGF2 mRNA expression and elevated FGF2 protein expression and secretion into the culture medium in FPS cells and endometrial adenocarcinoma explants. The effect of PGF₂ on the expression and secretion of FGF2 could be abolished by treatment of FPS cells and endometrial tissues with an FP receptor antagonist (AL8810) and inhibitor of extracellular signal-regulated kinase (ERK; PD98059). Furthermore, we have shown that FGF2 can promote the expression of FGF2 and COX-2 and enhance proliferation of endometrial adenocarcinoma cells via the FGFR1 and ERK pathways, thereby establishing a positive feedback loop to regulate neoplastic epithelial cell function in endometrial adenocarcinomas.