The β-catenin/TCF4/p300 pathway is involved in early signalling fortrans-differentiation towards the morular phenotype of endometrial carcinoma cells, but little is known about the upstream regulators. Here we show that transcription factor early growth response 1 (Egr1) acts as an initial mediator through up-regulating the expression of TCF4 and p300. In an endometrial carcinoma cell line with abundant oestrogen receptor α, Egr1 expression at both mRNA and protein levels was significantly increased by serum and 17β-oestradiol stimuli. Serum-stimulated cells also showed increased expression of TCF4 and p300, while inhibition of Egr1 by specific siRNAs resulted in decreased expression. Transfection of Egr1 led to transactivation ofTCF4as well asp300genes, through specific binding to a promoter region, and thus in turn resulted in nuclear accumulation of β-catenin mediated by the up-regulating TCF4. The overexpression also caused inhibition of β-catenin/TCF4/p300-mediated transcription, probably through sequestration of p300. Egr1 promoter activity was increased by serum but not 17β-oestradiol, in contrast to the marked repression associated with TCF4, p300, and Egr1 itself, indicating that the regulation involves several feedback loops. In clinical samples, cells immunopositive for nuclear Egr1, as well as β-catenin and TCF4, were found to be sporadically distributed in glandular components of endometrial carcinoma with morules. A significant positive correlation between nuclear β-catenin and TCF4 was observed, but no such link was evident for Egr1, probably due to the existence of negative feedback regulation. Together, these data indicate that Egr1 may participate in modulation of the β-catenin/TCF4/p300 signalling pathway as an initial event duringtrans-differentiation of endometrial carcinoma cells, through its impact on several signalling networks. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.