title: Expression of a dominant negative estrogen receptor alpha variant in transgenic mice accelerates uterine cancer induced by the potent estrogen diethylstilbestrol.
abstract: 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<0.016). ERΔ3 did not inhibit the expression of the estrogen-responsive progesterone receptor and lactoferrin genes in the presence of ERα or modify their expression in ERα knockout (αERKO) mice. Higher circulating 17β-estradiol levels and non-classical signaling by ERΔ3 may be related to the earlier incidence of uterine cancer. These findings indicate that expression of this ERα variant can influence determining events in uterine cancer development and its natural occurrence in the human uterus would unlikely be protective.
authors.affiliation: Receptor Biology Group, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, United States. dr.vicki.davis@gmail.com
authors.forename: Vicki L
authors.initials: VL
authors.lastname: Davis
authors.forename: Retha R
authors.initials: RR
authors.lastname: Newbold
authors.forename: John F
authors.initials: JF
authors.lastname: Couse
authors.forename: Sheri L
authors.initials: SL
authors.lastname: Rea
authors.forename: Katie M
authors.initials: KM
authors.lastname: Gallagher
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Hamilton
authors.forename: Eugenia H
authors.initials: EH
authors.lastname: Goulding
authors.forename: Wendy
authors.initials: W
authors.lastname: Jefferson
authors.forename: E M
authors.initials: EM
authors.lastname: Eddy
authors.forename: Bill C
authors.initials: BC
authors.lastname: Bullock
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Korach
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002273:Carcinogens / Q000633:toxicity*; D004054:Diethylstilbestrol / Q000633:toxicity*; D004958:Estradiol / Q000097:blood; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D004967:Estrogens / Q000633:toxicity*; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011374:Progesterone / Q000097:blood; D014594:Uterine Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism
chemical_list: D002273:Carcinogens; D047628:Estrogen Receptor alpha; D004967:Estrogens; D011374:Progesterone; D004958:Estradiol; D004054:Diethylstilbestrol