Neonatal tamoxifen treatment of mice leads to adenomyosis but not uterine cancer.

Tamoxifen is contraindicated during pregnancy but many births have been reported in breast cancer patients taking this drug and numbers might be expected to increase with FDA approval of tamoxifen for risk reduction in women at high, risk of breast cancer. The neonatal mouse, exquisitely sensitive to xenobiotic estrogens, has been used to investigate the effects of short-term oral dosing with tamoxifen (1 mg/kg on days 2-5 after birth) on long-term changes in uterine pathology and gene expression. Increased adenomyosis incidence and severity was evident in the tamoxifen-treated mice with increasing age. Uterine weights in treated mice remained lower than the corresponding controls up until 9 months, after which they became greater but during life-time studies (up to 36 months), there was no development of uterine tumours. Pathological examination of uterine tissues showed there to be extensive down-growth of endometrial glands and stroma into thickened, abnormal myometrium that had disorganised fascicles of smooth muscle and increased interstitial collagen deposition. In advanced cases, the endometrial epithelium showed mild degrees of focal hyperplasia and squamous metaplasia but no atypical cytology suggestive of premalignant change. Microarray analysis of uterine RNA taken at 1.5, 3, 6, 9 and 12 months showed from 4500 ESTs, only 12 genes were continuously over-expressed by tamoxifen treatment over this time, while none was continuously down-regulated. Up-regulated genes include those for nerve growth factor (Ngfa), cathepsin B (Ctsb), transforming growth factor beta induced (Tqfbi) and collagens (Colla1, Colla2). Results provide a basis for understanding the mechanism for tamoxifen induced tissue remodelling and the development of adenomyosis.