Biological responses of tamoxifen in the fetal and newborn vagina and uterus of the guinea-pig and in the R-27 mammary cancer cell line

Abstract

The biological and morphological responses of tamoxifen were studied in two models: (I) the uterus and vagina of fetal and newborn guinea-pigs; (II) R-27 cells—a mammary cancer cell line (tamoxifen resistant) derived from the MCF-7 cancer cell line. 1. (I) Tamoxifen (TAM) alone or in combination with estradiol (E 2) was administered to pregnant (50–52 days of gestation) or to newborn (2-day-old) guinea-pigs for a long period (12 days). TAM alone produced a great trophic effect on the uterus and vagina which was markedly enhanced when TAM was administered together with E 2. Histological studies showed that TAM provokes morphological changes in both the endometria and the myometria and this effect was also greater when TAM was administered together with E 2. In the fetal uterus and vagina, the ultrastructural studies showed that TAM induces morphological alterations in different cytoplasmic organelles. This effect was much more intense in newborns where TAM provoked a significant vacuolization of the epithelial cells. Concerning progesterone receptor (PR) in the fetal or newborn tissues (uterus or vagina) TAM provoked a less intense effect than those provoked by E 2, but TAM did not block the effect provoked by E 2. It was observed that [ 3H]TAM binds specifically to the estrogen receptor (ER) of fetal guinea pig uterus and this complex is partially recognized by a monoclonal antibody which recognizes the activated form of this receptor, supporting the suggestion that the biological action of TAM is mediated by the ER. 2. (II) The biological and ultrastructural effects provoked by TAM (1 × 10 −6 M), estriol (E 3) (5 × 10 −8 M) and the combination of TAM + E 3 were studied in the R-27 mammary cancer cell line in culture. E 3 stimulated the PR content by 7–10 times. However, TAM did not provoke a significant decrease in the concentration of PR, and in the mixture of TAM + E 3 the concentration of PR was of the same order as that in E 3 treatment. Ultrastructural observations indicate an intense concentration of ribosomes in the pericytoplasmic area after exposure to E 3 and with exposure to TAM an increase in vacuoles and a significant enlargement of the size of the mitochondria were observed. It is concluded that TAM in the target tissues of fetal and newborn guinea pigs acts as a real estrogen and in the R-27 mammary cancer cell line TAM does not block the effect provoked by E 3, however it does provoke intense ultrastructural modifications.