The use of the antiestrogen tamoxifen for breast cancer management, although generally well tolerated, is linked to an increase in uterine pathologies in a high number of postmenopausal women receiving the drug. This effect is thought to be due to estrogenic stimulation of the uterine endometrium by the antiestrogen; however, the molecular mechanism underlying the uterotrophic activity of tamoxifen and the uterine cellular compartments that respond to the drug have not been clearly established. In this study, we determined which of the several uterine tissues (myometrium, stroma, and luminal and glandular epithelium) demonstrated chronic overexpression of c- fos and the jun proto-oncogenes in response to tamoxifen. Uteri from tamoxifen-treated, castrated rats were examined histologically, and cell type-specific expression of c-fos, c-jun, jun-B, and jun-D was assessed using in situ hybridization. Treatment with tamoxifen resulted in uterine luminal and glandular epithelial hypertrophy and basally located nuclei by 36 h. Extreme uterine glandular and luminal epithelial cell hypertrophy persisted 7 days after administration of the drug. Expression of c-fos and jun-B messenger RNA was first detected in the luminal and glandular epithelial at 12-36 h post tamoxifen injection. Seven days after tamoxifen treatment, c- fos and jun-B messenger RNA levels were lower but still evident in the uterine endometrial epithelium. Tamoxifen completely repressed constitutive expression of c-jun in the uterine luminal epithelial cells by 12 h but, unlike estrogen, did not induce c-jun expression in the uterine myometrium. Expression of jun-D in the uterine glandular and luminal epithelia was observed at 12 h but not at 24 h post tamoxifen. These results support our working hypothesis that persistent overexpression of cellular oncogenes c- fos and jun-B in the uterine endometrial epithelium may contribute to the molecular mechanism underlying the uterine toxicity associated with chronic tamoxifen treatment.
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