Project 3: Estradiol and Progesterone Regulation of Transcription
Estrogens play critical roles in reproduction, cardiovascular health, neurophysiology as well as cancer progression and metastasis. The unifying goal of this project is to elucidate and understand the mechanism of estradiol (E2) and the estrogen receptor (ER) action in the brain, ovary, and breast. In recent years, it has also been shown that E2 has non-reproductive actions in the brain, such as enhancing synaptic plasticity and exerting neurotrophic and neuroprotective effects. Estradiol action mediated by ERα protects neurons in the cortex from cell death caused by middle cerebral artery occlusion. Very little is known about how ERα is regulated in the brain, either during development or after injury. Preliminary data demonstrates that the promoter of the ERα gene is methylated in the rat cortex prior to injury and is demethylated after injury when ERα mRNA expression increases. Thus, in the proposed studies, we will utilize a rodent model system to test the hypothesis that ERα mRNA expression in the cortex is regulated by epigenetic mechanisms following an ischemic injury. The project by Dr. Wilson investigates the regulation of ERα mRNA expression by epigenetic modification in an in vitro cortical explant model of ischemic injury and in a middle cerebral artery occlusion model of ischemic injury in vivo. Utilizing organotypic explant cultures we will determine the effect of ischemia on the expression and methylation status of ERα. We will also examine the composition of the ERα promoter by chromatin immunoprecipitation and assess the role of GADD45 in the demethylation of ERα in GADD45 null mice.
In the ovary, rising estrogen during the follicular phase drives normal oocyte and follicular development. However in polycystic ovary syndrome (PCOS) normal follicular development is compromised. PCOS is a leading endocrine disorder in women. Patients with PCOS display a cohort of endocrine and fertility defects including polycystic ovaries, hyperandrogenism, anovulation and an array of metabolic diseases. While the pathophysiology of PCOS is relatively well characterized, the etiology is poorly understood, mainly due to the lack of a well-defined animal model to study this disease. Dr. Ko has launched a project to develop a genetically modified animal model of PCOS. To achieve this goal, he has first generated a theca-specific Esr1KO (thEsr1KO) mouse using cre-lox technology. The thEsr1KO mice display characteristics of PCOS. The overall goal is to determine physiological and molecular characteristics of this PCOS model.
The role of E2 and the activation of ER in breast cancer are well documented. Inhibitors of ER transactivation and E2 production are currently part of the arsenal available to clinicians and their patients to treat breast cancer. We have recently shown that ERα interacts with another nuclear receptor, the peroxisome proliferator-activated receptor gamma 1 (PPARγ1). This receptor is the presumed target of the thiazolidinedione class of antidiabetic drugs. Preliminary data demonstrates that the interaction of PPARγ1 and ERα provides a novel therapeutic target for the treatment of breast cancer. The goal of these studies is to define how this interaction drives the process of metastasis in breast cancer cells in animal models.
Project 3 investigators: