Mechanisms of estrogen sensitivity in the human endometrium Public Deposited

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  • March 21, 2019
  • Lewis, Terrence Dairon
    • Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine
  • Endometrial cancer is the most common gynecologic malignancy, and a major cause of morbidity and mortality in women in the Western World. The American Cancer Society estimates that 41,200 cases will be diagnosed and 7,350 deaths will result from endometrial cancer in the United States in 2007. Unopposed estrogen exposure is the primary etiologic risk factor for developing this disease. However, the effects of estrogen and its receptors are not well defined within the human endometrium. The principal goal of this dissertation was to understand the individual contributions of the estrogen receptors (ERs) α and β within epithelial cells of the endometrium. To this end, three specific aims were developed to help further our understanding of the functions of these receptors in this tissue: (1) evaluate the expression of the receptors in normal, hyperplastic, and malignant tissue, (2) evaluate the effects of the receptor subtypes on the estrogen-inducible placental alkaline phosaphatase (ALPP) gene, and (3) to evaluate the effects of the receptors on proliferation of endometrial adenocarcinoma cells. Findings from the first aim indicate that an alteration in the normal ERα/ERβ ratio takes place in the stromal and epithelial compartments of the endometrium at the pre-malignant (hyperplastic) state. We believe that this change may be a key step that permits the endometrium to produce an exaggerated response to estrogens. Further studies evaluating the effects of the receptors on the ALPP gene used highly specific agonists of the estrogen receptors, PPT and DPN, along with cell lines expressing one receptor or the other. These studies reveal that ERα, and not ERβ, is responsible for the upregulation of ALPP. Further studies utilizing inhibitors of both MAP-Kinase and (PI)3-Kinase, revealed that the upregulation of ALPP is at least in part due to these signaling pathways within this model system. In our final aim we learned that ERα, and not ERβ, is involved in estrogen-induced proliferation of endometrial epithelial cells. Furthermore, ERβ acts as an inhibitor of proliferation within this tissue by possibly inhibiting the cell cycle by regulating key components of the cell cycle machinery.
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  • In Copyright
  • Kaufman, David
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  • University of North Carolina at Chapel Hill
  • Open access

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