Mechanisms by which steroid hormone receptor levels and functionality are controlled represent the focus of these studies. Model systems will be used in which we can examine receptor regulation by steroid hormones themselves, by peptide hormones, and by a class of compounds that may directly interfere with nuclear interactions of steroid-receptor complexes. The first system utilizes estrogen- and androgen-responsive tissues of the rat (primarily uterus, ventral prostate and anterior pituitary) to probe the dynamics of estrogen and androgen receptor turnover as influenced by the respective favored classes of steroid hormones themselves. A key feature of these studies at their present stage of development is the painstaking and systematic analysis of fluctuations in all populations of intracellular receptor. An off- shoot of this work has been the description of a discrete set of high affinity microsomal binding sites that are specific for steroid hormones and appear to mask microsomal acceptor sites for classical steroid-receptor complexes, thus being capable of regulating intranuclear levels of these complexes. In the next phase of these investigations, we will define acceptor specificity, explore the function of the microsomal binders as receptors for elicitation of extra-genomic actions of steroids, and, using monoclonal antibodies to the estrogen receptor, probe the origin and turnover of these proteins. Localization within specific organelles and initial attempts at purification will also be undertaken. The second major system, receptor control by peptide hormones, will continue to be addressed by the prolactin-mammary gland estrogen receptor interplay. We will use viral infection studies to investigate a correlation between levels of MMTV expression and sensitivity of mammary tissue to prolactin as a regulator of estrogen receptor activity. We will continue to study the mechanism by which prolactin regulates these receptors, concentration on differential nuclear binding affinities of prolactin-induced vs direct-estrogen-induced receptors, under conditions where graded responses can be engendered. We will begin to look for other factors involved in receptor regulation in this tissue. The third system involves modulation of steroid-receptor complex interactions at the nuclear level by agents which may interact directly with DNA to alter receptor binding to its effector sites. We have at hand a natural product that prevents formation of estrogen-responsive populations of mammary tumors by regulating receptor activity without direct interaction with the receptor. This may represent a novel form of receptor activity regulation.
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