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

Abstract

Tamoxifen was administered orally to neonatal rats on days 2-5 after birth and the subsequent effects on the uterus were characterized, morphometrically, over the following 12 months. Tamoxifen inhibited development of the uterus and glands in the endometrium, indicating a classical oestrogen antagonist 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 absence of any oestrogen agonist effect in the uterus. This demonstrates that an oestrogen agonist effect is not an absolute requirement for the carcinogenic effect of tamoxifen in the reproductive tract of the rat. The unopposed oestrogen agonist effect of tamoxifen on the endometrium may not be the only factor involved in the development of endometrial cancers. It is possible that tamoxifen causes these tumours via a genotoxic mechanism similar to that seen in rat liver. However, using (32)P-post-labelling we failed to find evidence of tamoxifen-induced DNA adducts in the uterus. Tamoxifen may affect 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 chemopreventative may have an increased risk of vaginal/cervical cancer, as well as endometrial cancer.

Comparisons of the effects of tamoxifen, toremifene and raloxifene on enzyme induction and gene expression in the ovariectomised rat uterus

“…ER was localised in both the glandular and luminal epithelial cells and the myometrium (Fig. 6A) confirming earlier studies (Carthew et al 1999). The localisation of uterine ER has not previously been described; we found it to be expressed in a similar distribution to that of ER (Fig.…”

“…The endometrial epithelium was predominantly cuboidal. Compared with controls, the uteri from rats treated with tamoxifen showed expansion of the myometrium and endometrial stroma as described previously (Carthew et al 1999). Compared with controls ( Fig.…”

Adrenomedullin inhibits hypoxic cell death by upregulation of Bcl-2 in endometrial cancer cells: a possible promotion mechanism for tumour growth

“…TAM is used for the treatment of breast cancer and is being evaluated as a prevention agent in women at high risk of developing the disease (Cuzick, 2000). A major concern is the proliferative e ect of TAM on the endometrium, which is associated with a 2 ± 7-fold increased risk of endometrial cancer for long-term tamoxifen users (Barakat, 1996;Bergman et al, 2000;Carthew et al, 2000). The mitogenic and antiapoptotic properties of ADM point to this peptide being a mediator of tamoxifen's adverse endometrial e ects.…”

“…In addition, we reported the presence of ADM in human endometrium where it was upregulated by the nonsteroidal antiestrogen tamoxifen (TAM) (Zhao et al, 1998). TAM, the long term endocrine treatment of choice for selected patients with breast cancer, is known to induce proliferative changes of the endometrium, increasing the risk of developing endometrial cancer (Bergman et al, 2000;Carthew et al, 2000). Recent evidence of a role for ADM in vascular development has come from the ADM knockout mouse that shows extreme hydrops fetalis and cardiovascular abnormalities (Caron and Smithies, 2001).…”

Tamoxifen induction of angiogenic factor expression in endometrium

“…Tamoxifen is currently being evaluated as a chemopreventative agent in healthy women at risk from the disease (Cuzick, 2000;Dalton and Kallab, 2001). One of the most significant complications of long-term TAM use is the development of endometrial cancer with up to a 7.5-fold increase in risk (Bergman et al, 2000;Carthew et al, 2000;Mourits et al, 2001). The increasing use of TAM, especially in healthy young subjects with no history of cancer, means that it is essential to improve our understanding of the mechanisms by which it exerts its adverse endometrial effects.…”