Carcinogenesis, Vol 18, 2293-2298, Copyright © 1997 by Oxford University Press
RR Newbold, WN Jefferson, E Padilla-Burgos and BC Bullock
The induction of preneoplastic and neoplastic lesions by the widely used
antiestrogen Tamoxifen was studied in female mice. Outbred CD-1 mice were
treated with Tamoxifen (1, 2, 5, 10, 25 or 50 microg/pup/day) for the first
5 days after birth. At 14-17 months, reproductive tract tissues were
examined for pathological changes. In the ovary, corpora lutea were lacking
while cysts were quite common in Tamoxifen-exposed mice at all doses;
cystadenomas were seen in two mice. Structural malformations and epithelial
hyperplasia of the oviduct were seen in 100% of the treated mice.
Malformations of the uterus, cervix, and vagina were also seen. Excessive
vaginal keratinization was not a common feature although vaginal adenosis
was observed more often after Tamoxifen treatment than previously reported
after similar treatment with diethylstilbestrol (DES). The most striking
histological features, however, were seen in the uterus. One hundred
percent of the Tamoxifen- treated mice at all doses exhibited uterine
hypoplasia with focal areas of basal cell hyperplasia in the lining
endometrium. Progressive cellular atypias were seen in the lining
endometrium ranging from atypical hyperplasia to uterine adenocarcinoma;
the highest incidence of uterine adenocarcinoma was 7/14 (50%) observed in
the Tamoxifen 10 microg/pup/day dose group. No similar tumors were observed
in corresponding control mice. The induction of atypical uterine
hyperplasia and adenocarcinoma combined with other abnormalities observed
in genital tract structure following neonatal treatment with Tamoxifen
suggests the developing reproductive tract is exquisitely sensitive to
perturbation by compounds with hormonal activity. These studies provide the
basis for future investigation into the mechanisms of Tamoxifen's
carcinogenic effects in experimental animals, and to the risk benefit
analysis for the prophylactic use of Tamoxifen in healthy women who are at
risk of developing breast cancer.
ARTICLES
Uterine carcinoma in mice treated neonatally with tamoxifen
Laboratory of Toxicology, Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
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