CONTRASTING EFFECTS OF TAMOXIFEN AND ICI-182-780 ON ESTROGEN-INDUCED CALBINDIN-D9K GENE-EXPRESSION IN THE UTERUS AND IN PRIMARY CULTURE OF MYOMETRIAL CELLS

Antiestrogens have a large range of tissue- and promoter-specific actions, many of which still remain unclear, particularly in the uterus. Thus, we have analyzed the effects of two antiestrogens, tamoxifen (TAM) and ICI 182 780 (ICI) on the uterine estrogen-responsive gene calbindin-D9k (CaBP9k), in the ovariectomized rat uterus, and in primary cultures of myometrial cells. In the ovariectomized rat uterus, estradiol (E(2)) or E(2) plus TAM induced CaBP9k mRNA to the same levels in 6h. Rats given TAM alone had the same mRNA concentration, but maximal induction was obtained later, 12h after injection. ICI alone did not induce CaBP9k gene expression. Rats given E(2) plus ICI had low uterine CaBP9k mRNA levels at 6-12h that became undetectable at 24h. Thus ICI has a full antagonistic effect on E(2)-induced CaBP9k gene. Estradiol receptor (ER) assays showed that TAM had a partial antagonist effect, while ICI had a full antagonist effect on the ER. We also analyzed the effect of TAM and ICI on CaBP9k gene expression in primary cultures of myometrial cells. The effects were similar to those observed in whole uterus. Thus, TAM has mixed effects, being an agonist for CaBP9k gene induction, and an antagonist for ER, ICI antagonizes the effects of E(2) on the CaBP9k gene in myometrial cells and in the intact uterus, but in,a way that does not involve a decrease in the cellular content of ER. Instead, it interferes with at least one of the events leading to transcriptional activation.