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）：我们的目标是研究芳基碳氢化合物受体（AHR）在乳腺癌进展中的作用，其长期目标是将AHR靶向预防性和治疗性乳腺癌。 AHR是一种由配体激活的转录因子，它介导了环境多环芳烃（PAH）的致癌作用。 AHR的PAH激活与癌变有关，通过诱导CYP1基因家族，随后产生反应性代谢产物和转录因子的激活。我们的实验室和其他人报告了晚期人类乳腺癌中组成症激活的AHR的高级表达。我们进一步表明，异位对AHR的表达足以诱导人类乳腺上皮细胞（HMEC）的恶性转化，而与PAH无关。我们在AHR转化的HMEC中产生的克隆细胞系表现出增强，上皮到间质转变以及增强的迁移和侵入性，如体外测量。因此，我们假设AHR的表达升高与乳腺癌的进展相关并预测，高AHR表达通过上调对肿瘤存活和侵入性至关重要的信号通路来促进侵入性乳腺癌的发展。要解决这一假设，我们的具体目的是1）测试AHR与表达相关性，使用SCID小鼠异种移植模型在体内发育和进展，通过原位植入型HMEC细胞系在体内的相关性，这些模型在正面上植入了EAR，并在表达AHR上进行乳腺肿瘤和转化的能力，以表现出乳腺肿瘤和转化的能力2）通过过表达AHR的细胞中AHR表达的siRNA敲低，然后评估其在体外和SCID小鼠中的致瘤潜力3），以确定肿瘤进展的哪些基因和信号传导途径被AHR激活了AHR的表达； 4）通过将人类乳腺肿瘤中的AHR表达与使用组织微阵列相关的疾病阶段和其他预后生物标志物，检查AHR的表达是否普遍上调。拟议的研究将定义AHR在浸润性乳腺癌进展中的因果作用。我们的发现可能将AHR验证为一种新的预测临床标记，并且是设计新型选择性抑制剂用于转移性乳腺癌治疗干预的独特目标。公共卫生相关性：本应用程序中提出的研究旨在解决和定义AHR在侵入性乳腺癌进展中的因果作用。这些研究的结果将有助于将AHR确定为乳腺癌转移性决定因素之一。因此将其确立为乳腺癌的独立生存预后因素。这些研究还将更好地理解AHR的分子作用及其在晚期乳腺癌中非配体非依赖性激活，从而为新型选择性抑制剂设计用于转移性乳腺癌的治疗性干预提供了独特的靶标。