Steroid hormone receptor regulation by various hormonal factors during mammary development and growth in the normal mouse

Abstract

The studies described herein are focused on the nature and regulation of estrogen receptors in normal mammary tissue, with the rationale that manipulation of these receptors is the sole basis for endocrine therapy of human breast cancer. Various features of this complex system have been uncovered by our studies. The presence of different forms of cytosol estrogen receptor, fluctuating in unison with glandular stimulation, results in differential responsiveness of the cells. Tissue that is relatively estrogen-starved presents its receptors in a form that avidly attract the limited available ligands and can hastily put them to use in the nucleus. In contrast, the receptor system in the highly stimulated state displays a sort of refractoriness to estrogen, being relatively sluggish in its responsiveness. Once formed, however, these latter complexes are probably far more effective in terms of eliciting estrogenic responses, since they have an enhanced affinity for DNA and a prolonged half-life. (Table; see text) Prolactin is clearly a very important mediator of the action of estrogen on the mammary gland estrogen receptors, presenting a tissue-specific difference in comparison with the regulation of the uterine estrogen-receptor system. An odd finding was that prolactin inhibits nuclear retention of the estrogen receptor (and probably the progesterone receptor), an effect that is counterproductive to its very strong positive action on the level of intracellular receptor. Perhaps prolactin is the gross effector of receptor fluctuation, allowing estrogen the privilege of dictating the degree of receptor function; indeed our data on the dose-responsiveness of estrogen action and the effects of bromocriptine indicate that a portion of the estrogenic stimulation is not mediated by prolactin. An interesting sidelight of these studies was the finding that high levels of bromocriptine, pharmacologic in terms of prolactin suppression, exhibited an inhibitory effect on nuclear retention of estrogen receptors that was independent of, and did not prevent subsequent elicitation of, the action of prolactin on the receptors. The role of prolactin in tumorigenesis is well established in experimental animals, but its role in the human disease is not clear. Although prolactin receptors have been measured in human breast cancer, there does not appear to be any distinguishable correlation with the presence of estrogen or progesterone receptors. While it is a bit premature to draw conclusions, initial trials of bromocriptine usage have not been supportive of beneficial effects of such treatment.(ABSTRACT TRUNCATED AT 400 WORDS)