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This study attempted to show directly how antiestrogens (tamoxifen and nafoxidine) affect the estrogen receptor (ER) in MCF-7 human breast cancer cells. The mechanisms of estrogen action through the unfilled ERs in both cytoplasm (Rc) and nuclei (Rn) of this cell line were contrasted with the effects of estradiol (E) and antiestrogens on receptor binding nuclear processing reactions and progesterone receptor (PgR) synthesis. Within 5 minutes E bound Rc and translocated it to the nucleus; E also bound Rn directly. Beginning 30 minutes after E and continuing for 3-5 hours a progressive depletion of about 70% of filled nuclear receptors (RnE) occurred without reappearance of unfilled receptor. From that point on the RnE levels stabilized a step coincident with PgR induction. The antiestrogens also bound Rc and Rn as demonstrated by in vitro competition studies and by exchange rates of tritiated E for ER complexed to antiestrogens in whole cells. However the nuclear antiestrogen receptor complexes were aberrantly processed; 3-5 hours after tamoxifen only 30% of nuclear-bound receptors were lost before nuclear receptor levels stabilized whereas nafoxidine-bound nuclear receptors were not processed at all. In spite of the only partial ER processing after tamoxifen PgR was induced as long as lower steady-state ER levels were maintained. When tamoxifen was removed total cell ERs returned to control levels as Rc were restored. Simultaneously PgR falls. Rc binding and translocation alone however are not sufficient for PgR induction since if nuclear processing fails PgR induction is prevented (as is the case with nafoxidine). These data suggest that nuclear processing steps may be integral to the function of estrogenic compounds as inducers of PgR.
Horwitz et al. (Wed,) studied this question.