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Non-genomic actions of estrogen in breast cancer

雌激素在乳腺癌中的非基因组作用

基本信息

批准号：
7225619
负责人：
ELLIS R LEVIN
金额：
$ 21.76万
依托单位：
SOUTHERN CALIFORNIA INST FOR RES/EDUC
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-02 至 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7225619
关键词：
1-Phosphatidylinositol 3-Kinase Aliquot BRCA1 Protein BRCA1 gene Binding Biological Breast Cancer Cell Cell Cycle Cell Cycle Progression Cell Cycle Stage Cell Nucleus Cell Proliferation Cell Survival Cell membrane Cells Condition Cultured Cells Cyclin D1 Cyclins DTR gene DUSP1 gene Dimerization Dominant-Negative Mutation EGF gene Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Estradiol Estrogen Nuclear Receptor Estrogen Receptors Estrogens Event Excision Family Fatty acid glycerol esters GTP Binding GTP-Binding Protein alpha Subunits GTP-Binding Proteins Genetic Transcription Genomics Goals Growth Hereditary Breast Carcinoma Human Immunoprecipitation In Situ In Vitro Insulin-Like Growth Factor I Lead Link Location M cell MCF7 cell MEKs Malignant Neoplasms Mammary gland Matrix Metalloproteinases Measures Mediating Membrane Mitogen-Activated Protein Kinases Modeling Nuclear Nuclear Envelope Nuclear Receptors Nude Mice PD-98059 Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide Phosphoric Monoester Hydrolases Phosphotransferases Production Protein Overexpression Proteins Publishing Radiolabeled Receptor Cell Receptor Cross-Talk Receptor Signaling Risk Signal Transduction Small Interfering RNA Stimulation of Cell Proliferation System Testing Transactivation Tyrphostin AG 825 Up-Regulation Western Blotting angiogenesis base cell type day dimer diphtheria toxin receptor heparin-binding EGF-like growth factor in vivo inhibitor/antagonist malignant breast neoplasm member migration mutant non-genomic novel prevent radiotracer receptor receptor function response tumor tumor growth wortmannin yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): Estrogen enhances the risk of developing breast cancer. Non-genomic effects of estrogen result from signal transduction originating at the membrane, in part from cross talk between ER and the EGF receptor. Cell based systems will establish that blocking E2-signaling through ERK and Pl3 kinase for 3 days substantially prevents the proliferation of cultured MCF-7 and ZR-75-1 (ER+) cells. G1 cell cycle targets and GI/S progression are ERK and Pl3K entrained. It is proposed that E2 interacts with BRCA1 to promote breast cancer. The ability of E2 to activate ERK will be shown to be down regulated by expression of wild type but not mutant BRCA1 in HCC-1937 cells (express a mutant BRCA1), co-transfected to express ER. This model will also determine whether wtBRCA1 can block the proliferative and ERK-inducing effects of E2, in cells cultured for 3 days. We will implicate the membrane receptor by expressing a dominant negative ER that only abrogates endogenous membrane ER function, and by targeting the E domain to the membrane. It is proposed that E2 binds the membrane ER, activates discrete G proteins that activate Src. Src activates specific matrix metalloproteinases that liberate HB-EGF and transactivates the EGFR or ErbB2. This leads to ERK and PI3K activation in breast cancer cells. This will be shown using dominant negative constructs SiRNA, and cells deficient for EGFR or ErbB2. We propose that the receptor must also dimerize to signal from the membrane, and we will use expression of a dimer mutant to show this. In-vivo, E domain targeted to membrane or nucleus are stably expressed in ER - breast cancer cells. These cells are injected into nude mice, and growth under estrogen-repleted conditions is determined. The goal is to define non-genomic actions of estrogen that could potentially be antagonized at the membrane, yet preserve the desirable effects of E2 in the nucleus.

描述（由申请人提供）：雌激素增加患乳腺癌的风险。雌激素的非基因组效应源于源于膜的信号转导，部分来自内质网和EGF受体之间的串扰。基于细胞的系统将证实，通过ERK和Pl3激酶阻断e2信号3天，可显著阻止培养的MCF-7和ZR-75-1 （ER+）细胞的增殖。G1细胞周期靶点和GI/S进展是ERK和Pl3K携带的。有人提出E2与BRCA1相互作用促进乳腺癌。在共转染表达ER的HCC-1937细胞（表达突变BRCA1）中，E2激活ERK的能力将被证明被野生型而非突变型BRCA1的表达下调。该模型还将在培养3天的细胞中确定wtBRCA1是否可以阻断E2的增殖和erk诱导作用。我们将通过表达一种显性负内源性内质网功能的内源性内质网，并将E结构域靶向到膜上，从而影响膜受体。有人提出E2结合膜内质网，激活可激活Src的离散G蛋白。Src激活特定的基质金属蛋白酶，释放HB-EGF并激活EGFR或ErbB2。这导致乳腺癌细胞中ERK和PI3K的激活。这将通过显性阴性结构体SiRNA和EGFR或ErbB2缺乏的细胞来证明。我们提出，受体也必须二聚体从膜信号，我们将使用二聚体突变的表达来证明这一点。体内，以膜或细胞核为靶点的E结构域在ER -乳腺癌细胞中稳定表达。将这些细胞注射到裸鼠体内，观察其在充满雌激素条件下的生长情况。目的是确定雌激素的非基因组作用，这些作用可能在膜上被拮抗，但在细胞核中保留E2的理想作用。