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Extranuclear estrogen receptor actions on endometrial cancer cell proliferation

核外雌激素受体对子宫内膜癌细胞增殖的作用

基本信息

批准号：
8294387
负责人：
TWILA A JACKSON
金额：
$ 27.72万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8294387
关键词：
1-Phosphatidylinositol 3-Kinase Biochemical Biological Assay Biological Models Birth Brain Breast Cancer Cell Growth Cancer Etiology Cell Cycle Cell Nucleus Cell Proliferation Cell membrane Cell model Cell physiology Cessation of life Child Chronic Co-Immunoprecipitations Complex Cyclin D1 Cytoplasm Disease Dissection Dominant-Negative Mutation Endometrial Endometrial Carcinoma Endometrial Hyperplasia Endometrium Environment Estradiol Estrogen Receptor Modulators Estrogen Receptors Estrogens Exposure to Fractionation Gene Expression Gene Expression Regulation Growth Health Homologous Gene Immediate-Early Genes Incidence Lead Ligands Liver MAP Kinase Gene Malignant Female Reproductive System Neoplasm Malignant Neoplasms Mediating Membrane Menarche Menstrual cycle Microscopy Mitogen-Activated Protein Kinases Mitogens Modeling Nuclear Nuclear Receptors Obesity Pathway interactions Phosphotransferases Progesterone Protein Biosynthesis Protein Kinase C Proto-Oncogene Proteins c-akt RNA biosynthesis RNA chemical synthesis Receptor Signaling Research Design Risk Factors Role SRC gene Scaffolding Protein Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Molecule Steroids Testing Tissues Uterus Woman cancer cell carcinogenesis cell growth cellular engineering hormone therapy immunocytochemistry inhibitor/antagonist insight non-genomic novel protein protein interaction protein-tyrosine kinase c-src response steroid hormone tensin transcription factor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Endometrial cancer is the most common invasive gynecological cancer and the fourth most common cancer in women in the US. Projections indicate that there will be 40,100 new cases and an estimated 7000 deaths in 2005. Estrogen (through the estrogen receptor) provides the primary proliferative signal in the endometrium and controls critical cellular processes such as proliferation and differentiation in many tissues including uterus, breast, liver, brain. The estrogen receptor has historically been thought of as a ligand-dependent transcription factor that exerts its effects by gene regulation. Recent observations suggest that the estrogen and other steroid hormones elicit rapid activation of cellular signal transduction pathways these are termed extranuclear actions. The general objectives of these studies are to define the mechanisms by which estrogen rapidly activates cytoplasmic signaling pathways, and to examine the functional role of these pathways in endometrial cancer cell proliferation. This will be accomplished by determining growth profiles of endometrial cancer cells engineered to express only transcriptionally inactive estrogen receptor in response to estrogen. Biochemical assays and pharmacological inhibitors will be employed to determine the contribution of estrogen dependent signaling pathways to endometrial cancer cell proliferation. The mechanisms by which the estrogen receptor activates mitogen activated (MAP) kinases, PI3 kinase, protein kinase C and other signaling molecules will emphasize dissection of the protein-protein interactions that occur rapidly at the plasma membrane in response to estrogen. The role of PTEN in negatively regulating extranuclear estrogen receptor actions and consequent endometrial cancer cell proliferation will be investigated. Type 1 endometrial cancer is considered to be primarily a disease of unopposed estrogen. Obesity promotes a chronic estrogen environment and correlates with a 20 fold increase in the incidence of endometrial cancer; therefore, the increase in societal obesity will likely lead to and increase in endometrial cancer. The proposed studies will offer important insights into a subset of estrogen receptor actions that may provide potential targets for endocrine therapies. PUBLIC HEALTH RELEVANCE: Endometrial cancer is the most common invasive gynecological cancer and causes 7500 deaths per year. Endometrial cancer is caused by chronic estrogen stimulation. Rising obesity rates, early menarche, later child birth and extended years of menstuation all contribute to increased lifetime exposure to estrogen, and therefore are predicted to lead to dramatic increases in endometrial cancer incidence. Understanding novel mechanisms of estrogen receptor action may provide new targets for endocrine therapies.

描述（由申请人提供）：子宫内膜癌是最常见的侵袭性妇科癌症，在美国女性中排名第四。预测表明，2005年将有40 100个新病例，估计有7 000人死亡。雌激素（通过雌激素受体）提供子宫内膜中的主要增殖信号，并控制许多组织（包括子宫、乳腺、肝脏、脑）中的关键细胞过程，如增殖和分化。雌激素受体历来被认为是一种配体依赖性转录因子，通过基因调控发挥其作用。最近的观察表明，雌激素和其他类固醇激素引起细胞信号转导途径的快速激活，这些被称为细胞核作用。这些研究的总体目标是确定雌激素快速激活细胞质信号通路的机制，并检查这些通路在子宫内膜癌细胞增殖中的功能作用。这将通过测定子宫内膜癌细胞的生长曲线来实现，所述子宫内膜癌细胞经工程改造仅表达对雌激素应答的转录失活的雌激素受体。将采用生物化学测定和药理学抑制剂来确定雌激素依赖性信号通路对子宫内膜癌细胞增殖的贡献。雌激素受体激活有丝分裂原激活（MAP）激酶，PI 3激酶，蛋白激酶C和其他信号分子的机制将强调解剖蛋白质-蛋白质相互作用，迅速发生在质膜上响应雌激素。PTEN在负调节细胞核雌激素受体作用和随后的子宫内膜癌细胞增殖中的作用将被研究。1型子宫内膜癌被认为主要是一种无对抗性雌激素的疾病。肥胖促进了慢性雌激素环境，并与子宫内膜癌发病率增加20倍相关;因此，社会肥胖的增加可能会导致子宫内膜癌的增加。拟议的研究将为雌激素受体作用的一个子集提供重要的见解，可能为内分泌治疗提供潜在的靶点。公共卫生相关性：子宫内膜癌是最常见的侵袭性妇科癌症，每年造成7500人死亡。子宫内膜癌是由慢性雌激素刺激引起的。肥胖率上升、初潮早、生育晚和月经期延长都导致一生中雌激素暴露增加，因此预计会导致子宫内膜癌发病率急剧增加。了解雌激素受体作用的新机制可能为内分泌治疗提供新的靶点。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rapid estrogen signaling negatively regulates PTEN activity through phosphorylation in endometrial cancer cells.

DOI：
10.1007/s12672-014-0184-z
发表时间：
2014-08
期刊：
Hormones & cancer
影响因子：
3
作者：
Scully MM;Palacios-Helgeson LK;Wah LS;Jackson TA
通讯作者：
Jackson TA

Endocrine disrupting activities of the flavonoid nutraceuticals luteolin and quercetin.

DOI：
10.1007/s12672-013-0150-1
发表时间：
2013-10
期刊：
Hormones & cancer
影响因子：
3
作者：
Nordeen SK;Bona BJ;Jones DN;Lambert JR;Jackson TA
通讯作者：
Jackson TA

DNA profiling analysis of endometrial and ovarian cell lines reveals misidentification, redundancy and contamination.

DOI：
10.1016/j.ygyno.2012.06.017
发表时间：
2012-10
期刊：
Gynecologic oncology
影响因子：
4.7
作者：
Korch C;Spillman MA;Jackson TA;Jacobsen BM;Murphy SK;Lessey BA;Jordan VC;Bradford AP
通讯作者：
Bradford AP