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

Abstract

MCF-7 cells of human breast cancer origin responded to estradiol (E) treatment with increased levels of progesterone receptor (PgR) showing that human breast cells which have undergone malignant changes can continue to synthesize a specific protein under hormone control. These results were obtained by studying the effects of addition and withdrawal of E on PgR synthesis and correlating this with estrogen receptor (ER) binding translocation nuclear processing reactions and restoration of unoccupied ER. In cells treated 1-5 days with E (.001-100 nM) basal PgR levels (.3-.7 pmol/mg of deoxyribonucleic acid) increased 3-6 fold. PgR response was dose-dependent with .1 nM E (a physiologic dose) the maximal effective dose. Growth and induction of PgR by .1 nM E was suppressed by an antiestrogen Tamoxifen at 10000-fold molar excess (1 mcgM) but was reversed by supraphysiological E (10 nM) which reduced the molar excess of Tamoxifen to only 100-fold. In this cell line ER unoccupied by hormone was 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 correlated with the extent of Rc binding and translocation and also with the extent of Rn binding. At .1 nM E 85% of Rc and Rn were depleted and PgR was maximally stimulated. The levels of PgR also paralleled processing of bound ER (RnE) appearing in the nucleus. Processing during which a new steady-state level of RnE was achieved appeared to be a saturable event. At low E doses despite Rc and Rn binding of E RnE failed to accumulate and total ER decreased. The loss approached 70% at .1 nM E. But at higher E doses some nuclear receptor remained unprocessed and RnE levels increased. The processing effect was rapid beginning within 10 minutes of E addition and completed by 5 hours. Processed RnE levels were seen before PgR induction and during maintenance of induced PgR states. In estrogen withdrawn cells PgR fell in parallel with end of processing and restoration of Rc and Rn.