TAMOXIFEN-INDUCED PROTOONCOGENE EXPRESSION PERSISTS IN UTERINE ENDOMETRIAL EPITHELIUM

The use of the antiestrogen tamoxifen for breast cancer management, al though generally well tolerated, is linked to an increase in uterine p athologies in a high number of postmenopausal women receiving the drug . This effect is thought to be due to estrogenic stimulation of the ut erine endometrium by the antiestrogen; however, the molecular mechanis m underlying the uterotrophic activity of tamoxifen and the uterine ce llular compartments that respond to the drug have not been clearly est ablished. In this study, we determined which of the several uterine ti ssues (myometrium, stroma, and luminal and glandular epithelium) demon strated chronic overexpression of c-fos and the jun proto-oncogenes in response to tamoxifen. Uteri from tamoxifen-treated, castrated rats w ere examined histologically, and cell type-specific expression of c-fo s, c-jun, jun-B, and jun-D was assessed using in situ hybridization. T reatment with tamoxifen resulted in uterine luminal and glandular epit helial hypertrophy and basally located nuclei by 36 h. Extreme uterine glandular and luminal epithelial cell hypertrophy persisted 7 days af ter administration of the drug. Expression of c-fos and jun-B messenge r 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 t he uterine endometrial epithelium. Tamoxifen completely repressed cons titutive expression of c-jun in the uterine luminal epithelial cells b y 12 h but, unlike estrogen, did not induce c-jun expression in the ut erine myometrium. Expression of jun-D in the uterine glandular and lum inal epithelia was observed at 12 h but not at 24 h post tamoxifen. Th ese results support our working hypothesis that persistent overexpress ion of cellular oncogenes c-fos and jun-B in the uterine endometrial e pithelium may contribute to the molecular mechanism underlying the ute rine toxicity associated with chronic tamoxifen treatment.