Estrogenic and antiestrogenic down-regulation of estrogen receptor levels: evidence for two different mechanisms.

Preincubation of MCF-7 cells with estradiol (E2) produces a decrease of 3H-E2 binding capacity ("processing"); the strong antiestrogen methylhydroxytamoxifen (MHT) is also effective but with a approximately 100 fold lower efficiency. Parallel immunological measurement of estrogen receptor contents of the cells (ER-EIA from Abbott) revealed that the mechanisms by which these ligands operate are not of the same nature. Thus, while E2 produced a loss of the ER peptide, MHT increased it; indicating an accumulation of a non-binding form of the receptor under its treatment. Measurement of the binding capacity of the cells for 3H-ORG 2058 showed a decrease of PgR concentration after pre-incubation with MHT which contrasted with the classical E2-induced increase of the receptor. MHT at relatively low concentrations also antagonised the E2-induced decrease of 3H-E2 binding capacity; this property did not result from a difference in chemical structure between the ligands since bisphenol a weak estrogenic analogue of MHT failed to show a similar antagonistic activity. This property confers to MHT the ability to reduce the efficiency of E2 to induce PgR. Finally, actinomycin D a known antagonist of the E2-induced processing was found to be totally ineffective towards the MHT processing. This clearly confirmed that the term "processing" covers at least two distinct mechanisms.