Estrogens and progestins are steroid hormones that regulate the differentiation and growth of many breast cancers and normal reproductive tissues. Cells that are responsive to these hormones contain specific nuclear receptor proteins which mediate the actions of these hormones. The proposed studies are directed toward understanding the turnover of these proteins, and the mechanisms by which these proteins are regulated. Enucleation of hormone-dependent, tumor-derived cell lines will be used to separate the site of receptor synthesis (presumably cytoplasm) from the site of steroid hormone action and what appears to be the site of the first step(s) in receptor inactivation and/or degradation (the nucleus), in order to separate the simultaneous processes of receptor synthesis from receptor inactivation/degradation. This new application of this technique will permit these processes to be studied separately, and will contribute new and direct answers to questions concerning how the levels of these receptors (and therefore how hormone-dependency) are maintained in these cancer cells, through regulation of receptor synthesis and/or receptor degradation rates. In addition, the routes of receptor synthesis and degradation will be examined with regard to the intracellular location of these routes, and examined for pre-receptor, modified receptor and/or hormone nonbinding intermediates. The proposed studies will address the mechanism involved in how these cells regulate hormone dependency through receptor protein turnover.
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