Prolactin mediation of estrogen-induced changes in mammary tissue estrogen and progesterone receptors.

Selective regulation of estrogen receptor (ER) content, distribution, and function has been studied in mouse mammary gland, as influenced by PRL and estradiol administration in vivo. In virgin female C3H+ mice, short-term treatment with PRL causes an apparent increase in the affinity with which activated ER binds to DNA. However, a contrasting effect of PRL to diminish nuclear accumulation of ER and progesterone receptors is consistently observed in PRL-treated mice. The ER-enhancing activity of PRL and the PRL mediation of estrogen stimulation of ER are more pronounced in C3H than in BALB/c mammary tissue, evidenced by the ability of bromocryptine (CB-154) to eradicate estrogen-stimulated appearance of ER in C3H, while having no effect on this parameter in the BALB/c animal. Uterine ER in either strain is independent of PRL and is stimulated with equivalent efficiency by estradiol. Stimulation of mammary gland ER activity by estradiol is dose responsive, being linear within the range of 0.25-5.0 micrograms/kg body weight. The simultaneous rise in cytosolic progesterone receptor binding activity is also linear over the same range. With respect to PRL responsiveness, ovariectomized adult (but not immature) mouse tissue shows a doubling of ER content with 10(3) or 10(4) micrograms/kg body weight, but no elevation with 10(2) or lower levels. The upper level is approximately equivalent to that seen in the intact or estrogen-replaced castrate mouse. High levels of PRL administered to these latter animal groups cause a secondary increase in ER activity. A PRL-independent component of estradiol-stimulated ER activity is demonstrable from experiments using various doses of CB-154 in animals treated with different levels of estradiol. High dosages of CB-154 superimposed on a highly inducing level of estradiol have a side effect of redistributing nuclear ER to the cytosol; sucrose gradient analyses of nuclear receptor levels demonstrate that this pharmacological action of CB-154 is not mediated through its PRL-suppressive effect. The suppression of nuclear ER by CB-154 is reflected in a loss of estrogen-induced progesterone receptor activity. The ability of tamoxifen to inhibit estrogen-stimulated progesterone receptor activity is appreciably curtailed by concomitant treatment with PRL. These results demonstrate that, of PRL and estradiol, PRL is the dominant factor in eliciting ER activity in mouse mammary gland. Basal conditions are established for quantifying the relative contributions of these and other modifiers of mammary tissue function at the molecular level, and for uncovering otherwise-masked differential dose-related effects of such agents.