Estrogen control of progesterone receptor in human breast cancer. Correlation with nuclear processing of estrogen receptor.

Some human breast cancers which contain estrogen receptors (ER) also contain progesterone receptors (PgR), whose presence may indicate that the ER remain responsive to estrogen and can still control specific protein synthesis. To demonstrate a direct role for ER we have used the human breast cancer cell line, MCF-7, which contains ER and low PgR levels. We have studied the effects of addition and withdrawal of estradiol on PgR synthesis and correlated this with ER binding, translocation, nuclear processing reactions, and restoration of unoccupied ER. In cells treated 4 to 5 days with estradiol(O.001 to 100 nx), basal PgR levels (0.3 to 0.7 pmollmg of HNA) increase 3to &fold. The PgR response is dose-dependent; 0.1 nM estradiol, a physiological dose, is maximally effective. Growth and induction of PgR by 0.1 mw estradiol are suppressed by an antiestrogen Tamoxifen at lO,OOO-fold molar excess (1 PM), but reversed by supraphysiological estradiol (10 nM) which reduces the molar excess of Tamoxifen to only loo-fold. In MCF-7, ER unoccupied by hormone is not restricted to the cytoplasm (Rc) since a portion of the cellular receptor can also be found in the nucleus in unoccupied form (Rn). The level of PgR induction correlates with the extent of Rc binding and translocation and also with the extent of Rn binding. At 0.1 nM estradiol, 85% of Rc and Rn are depleted and PgR is maximally stimulated. The levels of PgR also parallel processing of bound estrogen receptor (RnE) appearing in the nucleus. Processing, during which a new steady state level of RnE is achieved, appears to be a saturable event. At low estradiol doses, despite Rc and Rn binding of estradiol, RnE fails to accumulate and total ER decreases. The loss approaches 70% at 0.1 nM estradiol. However, at higher estradiol doses, some nuclear receptor remains unprocessed and RnE levels increase. The processing effect is rapid, beginning within 10 min of estradiol addition and completed by 5 h. Processed RnE levels are seen prior to PgR induction and during maintenance of induced PgR states. In estrogen withdrawn cells, PgR fall