title: Accelerated onset of uterine tumors in transgenic mice with aberrant expression of the estrogen receptor after neonatal exposure to diethylstilbestrol.
abstract: The role of estrogen and the estrogen receptor (ER) in the induction and promotion of tumors was investigated by using transgenic MT-mER mice, which overexpress the ER. It was hypothesized that because of this abnormal expression of the ER, the reproductive-tract tissues of the MT-mER mice may be more susceptible to tumors after neonatal exposure to the potent synthetic estrogen diethylstilbestrol (DES). Normally non-estrogen responsive tissues that may have expressed ER as a result of the transgene were also studied for DES-induced tumors. Wild-type and MT-mER littermates were treated with 2 micrograms/pup/d DES 1-5 d after birth and then killed at 4, 8, 12, and 18 mo of age. The DES-treated MT-mER mice demonstrated a significantly higher incidence of uterine adenocarcinoma at 8 mo (73%) than the DES-treated wild-type mice (46%). The tumors of the MT-mER mice were often more aggressive than those in the wild-type animals. These tumors were also preceeded at 4 mo by a significantly higher incidence of the preneoplastic lesion atypical hyperplasia in the MT-mER mice (26% compared with 0% in the wild-type mice). Other DES-induced abnormalities were observed at equal rates in the wild-type and MT-mER mice. Although no tumors were observed in untreated wild-type females, a single untreated MT-mER female had uterine adenocarcinoma at 18 mo. These data indicate that the level of ER present in a tissue may also be a determining factor in development of estrogen-responsive tumors.
authors.affiliation: Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Couse
authors.forename: V L
authors.initials: VL
authors.lastname: Davis
authors.forename: R B
authors.initials: RB
authors.lastname: Hanson
authors.forename: W N
authors.initials: WN
authors.lastname: Jefferson
authors.forename: J A
authors.initials: JA
authors.lastname: McLachlan
authors.forename: B C
authors.initials: BC
authors.lastname: Bullock
authors.forename: R R
authors.initials: RR
authors.lastname: Newbold
authors.forename: K S
authors.initials: KS
authors.lastname: Korach
mesh_terms: D000230:Adenocarcinoma / Q000139:chemically induced* / Q000648:ultrastructure*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D003043:Cocarcinogenesis; D004054:Diethylstilbestrol / Q000633:toxicity*; D005260:Female; D006965:Hyperplasia / Q000139:chemically induced; D008679:Metaplasia / Q000139:chemically induced; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D011960:Receptors, Estrogen / Q000096:biosynthesis* / Q000378:metabolism; D014594:Uterine Neoplasms / Q000139:chemically induced* / Q000648:ultrastructure*; D014599:Uterus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D002273:Carcinogens; D011960:Receptors, Estrogen; D004054:Diethylstilbestrol