Expression of a dominant negative estrogen receptor alpha variant in transgenic mice accelerates uterine cancer induced by the potent estrogen diethylstilbestrol

► ERΔ3 transgenic mice express the mouse ERα variant lacking the second zinc finger. ► Many tissues express ERΔ3; a higher ratio of ERα to ERΔ3 occurs in the uterus. ► Neonatal diethylstilbestrol accelerated uterine cancer in ERΔ3 versus wild-type mice. ► Estrogen-responsive genes (Pgr, Ltf) are not modified by ERΔ3 in the uterus. ► 17β-Estradiol serum levels are higher in ERΔ3 than wild-type mice. ERΔ3 transgenic mice expressing a dominant negative estrogen receptor α (ERα) variant lacking the second zinc finger in the DNA binding domain were developed to examine its potential to inhibit estrogen action in vivo. To investigate if ERΔ3 expression influences uterine carcinogenesis, ERΔ3 transgenic mice were exposed to diethylstilbestrol (DES) on post-natal days 1–5. Neonatal DES treatment induced uterine adenocarcinomas in 81% of 8-month-old ERΔ3 mice compared to 49% of wild-type females (p