Uterine carcinoma in mice treated neonatally with tamoxifen

The induction of preneoplastic and neoplastic lesions by the widely usedantiestrogen Tamoxifen was studied in female mice. Outbred CD-1 mice weretreated with Tamoxifen (1, 2, 5, 10, 25 or 50 microg/pup/day) for the first5 days after birth. At 14-17 months, reproductive tract tissues wereexamined for pathological changes. In the ovary, corpora lutea were lackingwhile cysts were quite common in Tamoxifen-exposed mice at all doses;cystadenomas were seen in two mice. Structural malformations and epithelialhyperplasia of the oviduct were seen in 100% of the treated mice.Malformations of the uterus, cervix, and vagina were also seen. Excessivevaginal keratinization was not a common feature although vaginal adenosiswas observed more often after Tamoxifen treatment than previously reportedafter similar treatment with diethylstilbestrol (DES). The most strikinghistological features, however, were seen in the uterus. One hundredpercent of the Tamoxifen- treated mice at all doses exhibited uterinehypoplasia with focal areas of basal cell hyperplasia in the liningendometrium. Progressive cellular atypias were seen in the liningendometrium ranging from atypical hyperplasia to uterine adenocarcinoma;the highest incidence of uterine adenocarcinoma was 7/14 (50%) observed inthe Tamoxifen 10 microg/pup/day dose group. No similar tumors were observedin corresponding control mice. The induction of atypical uterinehyperplasia and adenocarcinoma combined with other abnormalities observedin genital tract structure following neonatal treatment with Tamoxifensuggests the developing reproductive tract is exquisitely sensitive toperturbation by compounds with hormonal activity. These studies provide thebasis for future investigation into the mechanisms of Tamoxifen'scarcinogenic effects in experimental animals, and to the risk benefitanalysis for the prophylactic use of Tamoxifen in healthy women who are atrisk of developing breast cancer.