Tamoxifen induces endometrial and vaginal cancer in rats in the absence ofendometrial hyperplasia

Tamoxifen was administered orally to neonatal rats on days 2-5 after birth and the subsequent effects on the uterus were characterized, morphometrical ly, over the following 12 months, Tamoxifen inhibited development of the ut erus and glands in the endometrium, indicating a classical oestrogen antago nist action. Between 24 and 35 months after tamoxifen treatment there was a significant increase in the incidence (26%) of uterine adenocarcinomas and a 9% incidence of squamous cell carcinomas of the vagina/cervix in the abs ence of any oestrogen agonist effect in the uterus, This demonstrates that an oestrogen agonist effect is not an absolute requirement for the carcinog enic effect of tamoxifen in the reproductive tract of the rat, The unoppose d oestrogen agonist effect of tamoxifen on the endometrium may not be the o nly factor involved in the development of endometrial cancers. It is possib le that tamoxifen causes these tumours via a genotoxic mechanism similar to that seen in rat liver. However, using (32)p-post-labeling we failed to fi nd evidence of tamoxifen-induced DNA adducts in the uterus, Tamoxifen may a ffect hormonal imprinting of oestrogen receptor responses in stem cells of the uterus, causing reproductive tract cancers to arise at a later time, in the same way as has been proposed for diethylstilbestrol. If these rodent data extrapolate to humans, then women who are taking tamoxifen as a chemop reventative may have an increased risk of vaginal/ cervical cancer, as well as endometrial cancer.