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 a nd promotion of tumors was investigated by using transgenic MT-mER mic e, which overexpress the ER. It was hypothesized that because of this abnormal expression of the ER, the reproductive-tract tissues of the M T-mER mice may be more susceptible to tumors after neonatal exposure t o 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 mu g/pup/d DES 1-5 d after bir th and then killed at 4, 8, 12, and 18 mo of age. The DES-treated MT-m ER mice demonstrated a significantly higher incidence of uterine adeno carcinoma 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 th e wild-type animals. These tumors were also preceeded at 4 mo by a sig nificantly higher incidence of the preneoplastic lesion atypical hyper plasia 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 untreat ed wildtype females, a single untreated MT-mER female had uterine aden ocarcinoma at 18 mo. These data indicate that the level of ER present in a tissue may also be a determining factor in development of estroge n-responsive tumors. (C) 1997 Wiley-Liss. Inc.