Estrogen control of progesterone receptor in human breast cancer. Correlation with nuclear processing of estrogen receptor
Horwitz, K.B.; McGuire, W.L.
Journal of Biological Chemistry 253(7): 2223-2228
1978
ISSN/ISBN: 0021-9258 PMID: 632265 Document Number: 442920
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, the human breast cancer cell line, MCF-7, which contains ER and low PgR levels, was used. The effects of addition and withdrawal of estradiol on PgR synthesis were studied and this was correlated with ER binding, translocation, nuclear processing reactions and restoration of unoccupied ER. In cells treated 4-5 days with estradiol (0.001-100 nM), basal PgR levels (0.3-0.7 pmol/mg of DNA) increase 3- to 6-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 nM estradiol are suppressed by an antiestrogen tamoxifen at 10,000-fold molar excess (1 .mu.M), but reversed by supraphysiological estradiol (10 nM) which reduces the molar excess of tamoxifen to only 100-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 n.MU. 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 n.MU. estradiol. 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 In estrogen withdrawn cells, PgR fall in parallel with end of processing and restoration of Rc and Rn.