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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：
7762137
负责人：
Sakina Elzebair Eltom
金额：
$ 36.63万
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/7762137
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 Biological Markers Bioluminescence Biomedical Research Breast Cancer Prognostic Factor 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 Image 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 Neoplasm Metastasis Oligonucleotide Microarrays Parents Pathway interactions Patients Peer Review Pharmacology Phosphotyrosine Population Preventive Prognostic Factor 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 Skiing 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 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 prognostic 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. PUBLIC HEALTH RELEVANCE: The proposed research in this application is designed to address and define the causal role of AhR in invasive breast cancer progression. Results from these studies will help identify the AhR as one of the breast cancer metastatic determinants; thus establishing it as an independent survival prognostic factor for breast cancer. The studies will also lead to a better understanding of the molecular action of AhR and its ligand-independent activation in advanced breast cancer, thus providing a unique target for the design of novel selective inhibitors for therapeutic intervention of metastatic breast cancer.

描述（由申请人提供）：我们的目的是研究芳香烃受体（AhR）在乳腺癌进展中的作用，长期目标是靶向AhR，用于乳腺癌的预防和治疗干预。AhR是一种配体激活的转录因子，介导环境中多环芳烃（PAH）的致癌作用. PAH激活AhR通过诱导CYP 1家族基因以及随后产生的反应性代谢产物和激活转录因子参与致癌作用。我们的实验室和其他人已经报道了组成性激活的AhR在晚期人类乳腺癌中的高水平表达。我们进一步表明，AhR的异位过表达足以诱导人乳腺上皮细胞（HMEC）的恶性转化，独立于PAH。我们产生的AhR转化的HMEC的克隆细胞系表现出增强的增殖，上皮间质转化和增强的迁移和侵袭力，在体外测量。因此，我们推测AhR的表达升高与乳腺癌进展相关并预测乳腺癌进展，并且AhR的高表达通过上调对肿瘤存活和侵袭性至关重要的信号通路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小鼠异种移植模型在体内测试AhR过表达与浸润性癌的发展和进展的相关性，通过原位植入过表达AhR的克隆HMEC细胞系并证明其形成乳腺肿瘤和转移性肿瘤的能力2）通过siRNA敲低过表达AhR的细胞中AhR表达，然后评估其体外和体内致瘤潜力，来研究AhR过表达在浸润性癌发生和进展中的因果作用。SCID小鼠3）确定哪些基因和肿瘤进展的信号传导途径被AhR过表达激活; 4）通过使用组织微阵列将人乳腺肿瘤中的AhR表达与疾病的阶段和其他预后生物标志物相关联来检查晚期人乳腺癌中AhR的表达是否普遍上调。这项拟议的研究将确定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会验证AhR作为一个新的预测性临床标志物和一个独特的目标，设计新的选择性抑制剂的治疗性干预转移性乳腺癌。公共卫生关系：本申请中的拟议研究旨在解决和定义AhR在浸润性乳腺癌进展中的因果作用。这些研究的结果将有助于确定AhR作为乳腺癌转移的决定因素之一，从而将其确立为乳腺癌的独立生存预后因素。这些研究还将导致更好地了解AhR的分子作用及其在晚期乳腺癌中的配体非依赖性激活，从而为设计用于转移性乳腺癌治疗干预的新型选择性抑制剂提供独特的靶点。