Role of estrogen receptor in endometrial cancer initiation and progression

雌激素受体在子宫内膜癌发生和进展中的作用

• 批准号: 8698284
• 负责人: Sanaz Memarzadeh
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8698284
• 关键词: Accounting; Adult; Affect; Age; Aging; Am 80; Back; Biological; Biological Assay; Cells; Chronic; Critical Pathways; Diagnosis; Disease; Endometrial; Endometrial Carcinoma; Endometrial Hyperplasia; Endometrial Neoplasms; Endometrial Stromal Cell; Endometrium; Epidemiologic Studies; Epithelial; Epithelial Cells; Epithelium; Estrogen Receptor 1; Estrogen Receptor 2; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Exposure to; Female; Genetic Recombination; Genital system; Gland; Grant; Growth Factor; Gynecologic; Harvest; Hormone replacement therapy; Hormones; Immunohistochemistry; Incidence; Irregular Menstruation; Laboratories; Lead; Ligands; Malignant Neoplasms; Mediating; Menstruation; Modeling; Mus; Musa plant; Natural regeneration; Oncogenic; Outcome; PTEN gene; Paracrine Communication; Pathway interactions; Patients; Population; Postmenopause; Progesterone; Radiation; Receptor Signaling; Recurrent disease; Refractory; Risk Factors; Role; Signal Pathway; Signal Transduction; Staging; Stimulus; Stress; Stromal Cells; System; Tissues; United States; Uterus; Veterans; War; Western Blotting; Woman; base; cancer initiation; chemotherapy; clinically relevant; combat; hormone therapy; in vivo; in vivo regeneration; mouse model; novel; outcome forecast; overexpression; paracrine; promoter; recombinase; response; therapeutic target; tumor; tumor progression; vector

DESCRIPTION (provided by applicant): Role of Estrogen Receptor in Endometrial Cancer Initiation and Progression Epidemiologic studies dating back thirty years demonstrated that activation of the estrogen receptor (ER) signaling pathway by unopposed estrogen is a risk factor for the formation of endometrial carcinoma. Despite this observation, critical questions remain unanswered. (1) Why do only subsets, and not all women, exposed to unopposed estrogen develop endometrial cancer? (2) What are the ER mediated mechanisms that can lead to the formation of endometrial cancer? (3) Where in the uterus are estrogenic effects mediated, endometrial epithelium and/or stroma? A major limitation in studying endometrial cancer has been a paucity of mouse models, predominantly due to a lack of endometrial epithelial cell-specific promoters. Recently we have had a breakthrough in my laboratory with the establishment of an in vivo endometrial regeneration model from dissociated populations of endometrial epithelium and stroma. This system can be used to assay two important biological parameters in isolated subpopulations of endometrial cells: response to cell autonomous and paracrine oncogenic stimuli. Cell autonomous activation of the PI3Kinase axis via deletion of PTEN or paracrine signaling by growth factors are two pathways implicated in the initiation and progression of endometrial cancer, but mechanisms through which each of these pathways can interact with estrogen receptor signaling has not been determined. While ER 1 and ER 2 are both expressed in the endometrium, based on functional studies ER 1 - the main focus of the outlined studies in this grant - is thought to be the predominant form of ER in this tissue. In this proposal, we plan to delineate the epithelial specific role of ER 1 in cooperation with cell autonomous and paracrine oncogenic signals in endometrial cancer. We hypothesize that activation of epithelial ER 1 can cooperate with cell autonomous signals such as PI3Kinase pathway activation. Signaling through ER 1 may be essential for the initiation of endometrial hyperplasia and cancer mediated by cell autonomous or paracrine oncogenic signals. Oncogenic paracrine growth factor signals may lead to ligand independent activation of ER 1, which may be a critical pathway for the progression of endometrial cancer to a hormone refractory state. Our specific aims are (1) Examine potential synergy between the activation of the PI3Kinase and the ER 1 signaling axes in the endometrium. Endometrial epithelial cells harvested from PTENloxP/loxP mice will be lentivirally infected with ER 1 and Cre- recombinase resulting in deletion of PTEN and over expression of ER 1. These cells will be placed in the in vivo endometrial regeneration model and their tumor forming capacity will be compared to controls. (2) Assess whether epithelial ER 1 is essential for the formation of endometrial hyperplasia or cancer. Using a Cre-loxP recombination system, ER 1 will be deleted in endometrial epithelia harvested from floxed ER 1 mice and their response to paracrine or cell autonomous oncogenic signals will be assessed. (3) Determine the role of paracrine growth factor signaling in the ligand dependent and independent activation of ER 1. Retroviral delivery vectors will be used for the expression of candidate growth factors in endometrial stromal cells. Growth factor expressing stromal cells will be recombined with adult dissociated endometrial epithelia and placed in the in vivo endometrial regeneration model. Western blot and immunohistochemistry will be used to assess activation of ER 1 signaling in control and growth factor over expressing regenerated grafts. Findings in this proposal can define the epithelial specific role of ER 1 signaling in the initiation and progression of endometrial cancer in conjunction with cell autonomous and paracrine oncogenic signals. Our findings could have critical implications for the subset of patients with endometrial tumors driven by the ER 1 signaling, in whom ER 1 could be a valid therapeutic target. Results of this proposal could be a step toward individualizing therapy for this common gynecologic malignancy in the growing population of female veterans.

描述(由申请人提供)： 雌激素受体在子宫内膜癌发生发展中的作用30年前的流行病学研究表明，雌激素受体(ER)信号通路的激活是子宫内膜癌形成的危险因素。尽管有这样的观察，关键的问题仍然没有得到回答。(1)为什么只有亚组，而不是所有女性，暴露在无竞争的雌激素下会患上子宫内膜癌？(2)雌激素受体介导的导致子宫内膜癌形成的机制是什么？(3)子宫内膜上皮和/或间质中的雌激素效应是介导的？研究子宫内膜癌的一个主要局限是缺乏小鼠模型，这主要是由于缺乏子宫内膜上皮细胞特异性启动子。最近，我的实验室取得了突破性进展，从分离的子宫内膜上皮和间质中建立了在体子宫内膜再生模型。该系统可用于检测分离的子宫内膜细胞亚群中的两个重要生物学参数：对细胞自主和旁分泌致癌刺激的反应。生长因子通过缺失PTEN或旁分泌信号自主激活PI3Kinase轴是参与子宫内膜癌发生和发展的两条途径，但这两条途径与雌激素受体信号通路相互作用的机制尚未确定。虽然ER 1和ER 2都在子宫内膜中表达，但根据功能研究，ER 1--本基金概述的研究的主要重点--被认为是该组织中ER的主要形式。在这个方案中，我们计划描述ER1在子宫内膜癌中与细胞自主和旁分泌致癌信号协同作用的上皮特异性作用。我们推测，上皮性ER-1的激活可能与PI3Kinase通路等细胞自主信号的激活协同作用。通过ER1的信号可能在细胞自主或旁分泌致癌信号介导的子宫内膜增生症和癌症的发生中起重要作用。癌基因旁分泌生长因子信号可能导致ER1的配体非依赖性激活，这可能是子宫内膜癌向激素不耐受状态发展的关键途径。我们的具体目标是(1)检测子宫内膜中PI3Kinase和ER1信号轴的激活之间的潜在协同作用。取PTENloxP/loxP小鼠子宫内膜上皮细胞，慢病毒感染ER1和Cre重组酶，导致PTEN缺失和ER1过度表达。将这些细胞置于在体子宫内膜再生模型中，比较它们的成瘤能力。(2)评估上皮ER-1是否在子宫内膜增生症或癌的形成中起重要作用。利用Cre-loxP重组系统，从ER 1小鼠的子宫内膜上皮中删除ER 1，并将评估它们对旁分泌或细胞自主致癌信号的反应。(3)确定旁分泌生长因子信号在ER1配体依赖和非依赖激活中的作用。逆转录病毒载体将用于子宫内膜间质细胞表达候选生长因子。表达生长因子的基质细胞将与成人分离的子宫内膜上皮重组，并放置在体内子宫内膜再生模型中。Western印迹和免疫组织化学将用来评估ER1信号在对照和生长因子过度表达再生移植物中的激活情况。这项研究的结果可以明确ER1信号与细胞自主和旁分泌致癌信号一起在子宫内膜癌的发生和发展中所起的特殊作用。我们的发现可能对ER1信号驱动的子宫内膜肿瘤患者亚群具有重要意义，在这些患者中，ER1可能是一个有效的治疗靶点。这项建议的结果可能是朝着在日益增长的女性退伍军人中对这种常见的妇科恶性肿瘤进行个体化治疗迈出了一步。