Downregulation of estrogen receptor gene expression by exogenous 17beta-estradiol in the mammary glands of lactating mice.

The biological actions of estrogen are mostly conveyed through interaction with the nuclear estrogen receptor (ER). Previous evidence indicated that estrogen participates in self-regulation through the modulation of the expression of its own receptors. However, the self-regulation of estrogen against ER in the mammary gland during established lactation has not yet been investigated. The present study evaluated ER gene expression in the lactating gland activated by large doses of 17beta-estradiol (E(2)). Repeated E(2) treatments dose-dependently decreased the gene expression of ER, especially its subtype ER-alpha mRNA, which was decreased to 10% of the vehicle-injected control by 1 mug E(2) injection, whereas it was decreased by 73% for another subtype, ER-beta. A single injection of 5 mug of E(2) drastically downregulated both ER genes within 12 hrs of injection, and they did not recover to pretreatment level within 48 hrs. Western blot analysis verified that E(2) treatment inhibited the phosphorylation of Stat5, which is a potent transcriptional regulator for ER mRNA. The present findings demonstrate that E(2) treatment decreases the gene expression of its own receptor in the mammary gland during galactopoesis and induces an apparent transition of the ER profile in the mammary gland during lactation into postlactation.