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The Aryl Hydrocarbon Receptor and Breast Cancer

芳基烃受体与乳腺癌

基本信息

批准号：
8470567
负责人：
Sakina Elzebair Eltom
金额：
$ 34.08万
依托单位：
MEHARRY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8470567
关键词：
Address Adhesions Affect Agar American American Association of Cancer Research Anchorage-Independent Growth Animals Area Aromatic Polycyclic Hydrocarbons Aryl Hydrocarbon Receptor Authorship BHLH Protein Biochemistry Biomedical Research Breast Carcinoma Cancer Biology Carcinoma Cell Cycle Cell Line Cell Survival Cells Clinical Markers Complement Comprehensive Cancer Center Core Facility Critiques DNA Damage Data Development Disease Doctor of Philosophy Educational workshop Environment Enzymes Epithelial Cells Estrogens Exhibits Faculty Feedback Funding Future Gene Expression Gene Family Generations Genes Genetic Transcription Genome Goals Grant Group Meetings Growth Guns HIV Human Implant In Vitro Journals Kentucky Laboratories Lead Ligands Link Mainstreaming Maintenance Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Mammary Neoplasms Mammary gland Manuscripts Matrigel Invasion Assay Measures Mediating Medical center Medicine Mentors Minority Modification Molecular Molecular Toxicology Monitor National Institute of General Medical Sciences Neoplasm Metastasis Oligonucleotide Microarrays Parents Pathway interactions Patients Peer Review Pharmacology Phosphotyrosine Population Preventive Intervention Prognostic Factor Prognostic Marker Protein Kinase Proteomics Publications Publishing Records Regulation Reporting Research Research Personnel Research Proposals Resource Sharing Role SCID Mice Series Signal Pathway Signal Transduction Signaling Pathway Gene Small Interfering RNA Societies Specimen Staging Structure Students Technology Testing Therapeutic Therapeutic Intervention Time Tissue Microarray Toxicology Training Tyrosine United States National Institutes of Health Universities Wisconsin Work Writing Xenograft Model activating transcription factor base bioluminescence imaging cancer initiation carcinogenesis career cell motility cell transformation chemical carcinogenesis density design epithelial to mesenchymal transition graduate student health disparity improved in vivo inhibitor/antagonist malignant breast neoplasm malignant phenotype medical schools medical specialties meetings member migration neoplastic cell novel oncology overexpression professor programs public health relevance receptor receptor expression research study symposium transcription factor tumor tumor progression tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Our objective is to investigate the role of the aryl hydrocarbon receptor (AhR) in breast cancer progression with a long-term goal of targeting AhR for preventive and therapeutic intervention of breast cancer. AhR is a ligand- activated transcription factor which mediates the carcinogenic effects of environmental polycyclic aromatic hydrocarbons (PAH). PAH activation of AhR is implicated in carcinogenesis through induction of CYP1 family of genes with subsequent generation of reactive metabolites and activation of transcription factors. Our laboratory and others have reported high-level expression of constitutively activated AhR in advanced human breast carcinomas. We further showed that ectopic over expression of AhR is sufficient to induce malignant transformation of human mammary epithelial cells (HMEC), independent of PAH. Our generated clonal cell lines of the AhR-transformed HMEC exhibited enhanced proliferation, epithelial-to-mesenchymal transition and enhanced migration and invasiveness, as measured in vitro. We therefore postulated that elevated expression of AhR correlates with and forecasts breast cancer progression and that high AhR expression promotes the development of invasive breast carcinoma by up-regulating signaling pathways critical for tumor survival and invasiveness. To address this hypothesis our specific aims are 1) To test the relevance of AhR over expression for development and progression of invasive carcinoma in vivo using SCID mice xenograft model, by orthotopically implanting clonal HMEC cell lines which over express AhR and demonstrating their ability to form mammary tumors and metastatic occults 2) To examine the causal role of the AhR over expression on the development and progression of invasive carcinoma by the siRNA knockdown of AhR expression in cells overexpressing AhR followed by assessing their tumorigenic potential in vitro and in SCID mice 3) To determine which genes and signaling pathways for tumor progression are activated by AhR over expression; 4) To examine whether the expression of AhR is universally upregulated in advanced human breast cancer, by correlating the AhR expression in human breast tumors with the stage of the disease and other prognostic biomarkers using tissue microarrays. The proposed research will define the causal role of AhR in invasive breast cancer progression. Our findings may validate the AhR as a new predictive clinical marker and a unique target for designing novel selective inhibitors for therapeutic intervention of metastatic breast cancer.

描述（由申请人提供）：我们的目标是研究芳烃受体（AhR）在乳腺癌进展中的作用，长期目标是针对乳腺癌进行预防和治疗干预。 AhR 是一种配体激活的转录因子，介导环境多环芳烃 (PAH) 的致癌作用。 PAH 激活 AhR 通过诱导 CYP1 基因家族以及随后产生反应性代谢物和激活转录因子而与癌发生有关。我们的实验室和其他实验室报告了在晚期人类乳腺癌中组成型激活的 AhR 的高水平表达。我们进一步表明，AhR 的异位过度表达足以诱导人乳腺上皮细胞 (HMEC) 的恶性转化，与 PAH 无关。我们生成的 AhR 转化 HMEC 克隆细胞系在体外测量时表现出增强的增殖、上皮间质转化以及增强的迁移和侵袭性。因此，我们假设 AhR 表达升高与乳腺癌进展相关并预测乳腺癌进展，并且 AhR 高表达通过上调对肿瘤生存和侵袭性至关重要的信号通路来促进浸润性乳腺癌的发展。为了解决这一假设，我们的具体目标是 1) 使用 SCID 小鼠异种移植模型，通过原位植入过度表达 AhR 的克隆 HMEC 细胞系并证明其形成乳腺肿瘤和转移性隐匿性的能力，测试 AhR 过表达与体内侵袭性癌发生和进展的相关性 2) 检查 AhR 过表达对侵袭性癌发生和进展的因果作用通过 siRNA 敲低过表达 AhR 的细胞中的 AhR 表达，然后在体外和 SCID 小鼠中评估其致瘤潜力 3) 确定哪些基因和肿瘤进展的信号通路被 AhR 过表达激活； 4) 通过使用组织微阵列将人类乳腺肿瘤中的 AhR 表达与疾病阶段和其他预后生物标志物相关联，检查 AhR 的表达在晚期人类乳腺癌中是否普遍上调。拟议的研究将确定 AhR 在浸润性乳腺癌进展中的因果作用。我们的研究结果可能验证 AhR 作为一种新的预测性临床标志物和设计用于治疗干预转移性乳腺癌的新型选择性抑制剂的独特靶点。