The role of ERα in the uterus during embryo implantation and in the ovary during ovarian tumorigenesis

Laws, Mary J.

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Description

Title

The role of ERα in the uterus during embryo implantation and in the ovary during ovarian tumorigenesis

Author(s)

Laws, Mary J.

Issue Date

2011-05-25T14:28:00Z

Director of Research (if dissertation) or Advisor (if thesis)

Bagchi, Indrani C.

Doctoral Committee Chair(s)

Bagchi, Indrani C.

Committee Member(s)

• Bagchi, Milan K.
• Cooke, Paul S.
• Flaws, Jodi A.

Department of Study

Comparative Biosciences

Discipline

VMS - Veterinary Biosciences

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• estrogen receptor alpha
• hypoxia-inducible factor 2 alpha
• uterus
• embryo implantation
• ovarian cancer
• ovarian tumorgenesis
• mouse model ovarian cancer

Abstract

The molecular actions initiated by the steroid hormone estrogen elicit a multitude of biological effects in physiological and pathophysiological processes. Estrogen acts via its cognate steroid hormone receptor, estrogen receptor alpha (ERalpha) or beta (ERalpha, to fulfill these biological processes. This dissertation investigates estrogen’s action via ERalpha in uterine physiology and ovarian pathophysiology and is written in two parts. The first part is an investigation of ERalpha and its downstream target Hif2alpha in the uterus during embryo implantation. The later part of the dissertation discusses the role that ERalpha plays in ovarian tumorigenesis. Both humans and rodents exhibit hemochorial placentation, an invasive form of embryo implantation which is characterized by intimate contact of the implanted embryo with maternal blood. Implantation is initiated when the embryo first attaches to the uterine epithelial cells and invades through these cells to the underlying stroma. This process triggers the uterine stromal cells to undergo proliferation and differentiation to form the decidua, a secretary maternal tissue that provides the necessary nutrients to support embryonic life prior to placentation. Through the development of knockout mouse models, it is known that ERalpha, the predominant estrogen receptor in the uterus, is essential for the embryo to attach to these cells prior to invasion. However, we have uncovered for the first time the essential role of ERalpha in uterine stromal cell differentiation during embryo implantation. We have developed a conditional knockout mouse model, termed ERalphad/d, which has ERalpha deleted in all cell types which express progesterone receptor (PR). By employing artificially induced decidualization we know that ERalpha in the uterine stromal cells is essential for proliferation and decidualization. To date very few molecules have been shown to be regulated by estrogen in the uterine stromal cells that are essential for decidualization. Our laboratory has shown that it is local estrogen production acting via ERalpha within the uterine stromal cells that drives and sustains the decidualization response. Furthermore this local estrogen production regulates Endothelial PAS Domain Protein 1 (EPAS1), also called Hypoxia-inducible Factor 2 alpha (Hif2alpha). Hif2alpha is a transcription factor that has been shown to be regulated by hypoxic conditions and regulates molecules essential for an angiogenesis response. In order to study the functional role of Hif2alpha we have created a conditional knockout of the Hif2alpha gene which has Hif2alpha knocked out in all cells expressing PR. This conditional knockout mouse, termed Hif2alphad/d, is infertile. During pregnancy embryos travel to the uterine lumen and attach to uterine epithelial cells. This attachment elicits an initial decidual response. This the first in vivo model to show that embryo attachment and not embryo invasion through the epithelial cells provokes a stromal cell decidual response. In absence of Hif2alpha stromal cells begin the process of decidualization and display alkaline phosphatase activity, a marker of differentiation. However, prolactin related protein (PRP), a decidual marker induced later in the decidualization process, is absent in the Hif2d/d uterus indicating that the terminal differentiation of stromal cells is compromised in absence of Hif2alpha. Furthermore without Hif2alpha in the stromal cells angiogenesis at the early stages of pregnancy is impaired as marked by a downregulation of an endothelial cell marker, PECAM. Understanding downstream molecules of Hif2alpha will undoubtedly give insight into the molecular pathways essential for implantation. The role that uterine ERalpha and its downstream target, Hif2alpha plays in the early phases of pregnancy will be the topic of chapter 2. The second part of this dissertation focuses on the role that ERalpha plays in the pathophysiology associated with ovarian tumorigenesis. We have generated an animal model which forms epithelial ovarian tumors with 100% penetrance. This animal model is a conditional knockout for the ERalpha, termed ERalphad/d. This animal shows a lack of ERalpha expression in the pituitary which leads to a lack of negative estrogen feedback on the hypothalamus-pituitary-ovarian axis resulting in high serum levels of luteinizing hormone, estradiol, progesterone and testosterone. Interestingly ovarian expression of ERalpha in this animal model remains intact. We have shown that by treating animals with letrozole, an aromatase inhibitor, that ovarian tumor volume is decreased compared to untreated animals, indicating a novel role of ERalpha in ovarian tumorigenesis. This animal model mimics the genetic profile of human serous epithelial ovarian carcinoma and provides a novel tool to study epithelial ovarian tumorigenesis for two reasons: 1) tumors form slowly over the course of the animal’s life mimicking human epithelial ovarian tumors and 2) ovarian tumors form due to a physiological perturbation and not a mechanical perturbation, such as intra-bursal injection to induce oncogene expression, further mimicking the human ovarian tumor formation. This animal model will aid in our understanding of how epithelial ovarian tumors form and will likely lead to the discovery of treatments and/or diagnostic tools for this disease.

Graduation Semester

2011-05

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Copyright 2011 Mary Jo Laws

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