Accelerated onset of uterine tumors in transgenic mice with aberrant expression of the estrogen receptor after neonatal exposure to diethylstilbestrol.
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.
Couse
J F
JF
Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Davis
V L
VL
Hanson
R B
RB
Jefferson
W N
WN
McLachlan
J A
JA
Bullock
B C
BC
Newbold
R R
RR
Korach
K S
KS
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
D002273:Carcinogens; D011960:Receptors, Estrogen; D004054:Diethylstilbestrol