of Work: Estrogen hormone action within target tissues involves the interaction of the hormonal substance with a receptor protein. The specificity and responsiveness of tissues to hormonal stimulation are governed in most part by the presence and biochemical action of this receptor protein. Nuclear localization of the receptor and its activity was increased by exposure to growth factors, suggesting a coupling of these two signaling pathways. Gene regulation studies using mutant receptors show that growth factors regulate activity through the N-terminus of the receptor while estrogen acts through the C-terminus. Receptor mutants also demonstrated that DNA binding is required for the coupling activation. Use of the estrogen receptor recessive mice has supported the coupling as an in vivo mechanism, since EGF treatment did not stimulate uterine DNA synthesis in the absence of a functional estrogen receptor. Characterization of the EGF signaling pathway in the mice indicates EGF receptor levels and functionally are not altered compared to controls. Estrogen receptor knockout mice (ERKO) have been generated and their use as an experimental model system for evaluating the role of ER-a in normal physiological endocrine function and hormonal carcinogenesis has shown that the mitogenic ligand independent activation of EGF in uterine tissue requires a functional estrogen receptor. Since ERKO mice have no mammary gland development, a test for the role of estrogen receptor in development of mammary tumors was developed. A cross of ERKO with a mammary sensitive mouse line (WNT-1) expressing the WNT-1 oncogene was produced. These data indicate that the WNT-1 oncogene does not require functional estrogen receptor to produce an epithelial cell specific mitogenic response. Additionally, these animals do develop tumors at approximately half the level as WT. These findings would oppose one earlier hypothesis that mammary tumors develop from hormone responsive tissues. ERKO male infertility was shown to be dependent on a progressive lesion of testicular semiferous tubule dysmorphogenesis resulting in a loss of germ cells and decreased sperm counts. The sperm present in ERKO males have low motility and are incapable of successful in vitro fertilization indicating that there are multiple effects in the male reproductive tract. The findings also clearly demonstrate a requirement for estrogen receptor action in normal male reproductive physiology. The first patient with estrogen insensitivity has been described and the loss of function gene mutations characterized for this clinical syndrome. A clinical evaluation of male infertility patients is underway for detection of ER gene mutations. As a means of extending the ERKO model evaluating the mechanism of environmental estrogen action ERKO mice were treated with genistein which also acts as a tyrosine kinase inhibitor and shows that uterine growth was not stimulated indicating genistein acts through the estrogen receptor for this response. However, suppression of lutenizing hormone (LH) was shown to be as effective in ERKO as WT mice indicating this estrogen response by genistein does not require the receptor as previously thought. Differences in gene responses to hormonal xenobiotics were also seen in some in vitro gene regulation studies. Using transactivation assay system trichlorobiphenol was shown to be more active than estradiol on the lactoferrin gene. Use of this estrogen responsive yeast system also tested the xenobiotic estrogen synergy concept and showed that using a variety of genes that synergy was not pparent and had no universal application to hormone responsive systems.
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