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: 8282596
• 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/8282596
• 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的起步和进展过程中的作用30年的流行病学研究表明，通过无反应的雌激素激活雌激素受体（ER）信号传导途径是形成子宫内膜癌的危险因素。尽管进行了观察，但关键问题仍未得到答复。 （1）为什么只有暴露于无反应的雌激素的亚群而不是所有妇女会发展出子宫内膜癌？ （2）ER介导的机制是什么，可以导致子宫内膜癌的形成？ （3）子宫中雌激素作用介导的，子宫内膜上皮和/或基质的位置？研究子宫内膜癌的主要局限性是小鼠模型的缺乏，主要是由于缺乏子宫内膜上皮细胞特异性启动子。最近，通过建立了从子宫内膜上皮和基质的分离群体建立一个体内子宫内膜再生模型，我们的实验室取得了突破。该系统可用于测定子宫内膜细胞孤立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。通过删除PTEN或通过生长因子对PTEN信号传导的细胞自主激活是与子宫内膜癌的起始和进展有关的两种途径，但是尚未确定这些途径可以与雌激素受体信号相互作用的机制。虽然ER 1和ER 2均在子宫内膜中表达，但基于功能研究ER 1-该赠款中概述的研究的主要重点 - 被认为是该组织中ER的主要形式。在此提案中，我们计划描述ER 1在子宫内膜癌中与细胞自主和旁分泌致癌信号合作的上皮特异性作用。我们假设上皮ER 1的激活可以与细胞自主信号（例如PI3Kinase途径激活）合作。通过ER 1的信号传导对于启动由细胞自主或旁分泌致癌信号介导的子宫内膜增生和癌症至关重要。致癌旁分泌生长因子信号可能导致ER 1的配体独立激活，这可能是子宫内膜癌向激素难治态发展的关键途径。我们的具体目的是（1）检查PI3Kinase的激活与子宫内膜中ER 1信号轴之间的潜在协同作用。从ptenloxp/loxp小鼠收获的子宫内膜上皮细胞将被ER 1慢性病感染，并将重物组合酶感染，导致PTEN删除并过度表达ER 1。这些细胞将放置在体内子宫内膜再生模型及其肿瘤形成能力中将其与对照组进行比较。 （2）评估上皮ER 1是否对于形成子宫内膜增生或癌症是必不可少的。使用CRE-LoxP重组系统，将在从Floxed ER 1小鼠中收获的子宫内膜上皮中删除ER 1，并评估它们对旁分泌或细胞自主性致癌信号的反应。 （3）确定旁分泌生长因子信号传导在ER 1的配体依赖性和独立激活中的作用。逆转录病毒递送向量将用于表达子宫内膜基质细胞中候选生长因子。表达基质细胞的生长因子将与成年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。蛋白质印迹和免疫组织化学将用于评估在表达再生移植物的控制和生长因子中ER 1信号的激活。该提案中的发现可以定义ER 1信号传导在子宫内膜癌的启动和进展中与细胞自主和旁分泌致癌信号的上皮作用。我们的发现可能对由ER 1信号传导驱动的子宫内膜肿瘤患者的子集具有至关重要的意义，ER 1可能是有效的治疗靶标。该提案的结果可能是对不断增长的女性退伍军人人口的这种常见妇科恶性肿瘤的个性化治疗的一步。