Research Project 1: Role of the Aromatic Hydrocarbon Receptor in the Etiology of

研究项目1：芳香烃受体在病因学中的作用

基本信息

批准号：
8143314
负责人：
David H Sherr
金额：
$ 21.64万
依托单位：
TUFTS UNIVERSITY BOSTON
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：
2010-09-15 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8143314
关键词：
3-Dimensional Advanced Malignant Neoplasm Animals Apoptosis Aromatic Polycyclic Hydrocarbons Binding Breast Cancer Model Breast Cancer Risk Factor CYP1A1 gene CYP1B1 gene Cell Line Cells Characteristics Chemicals Collaborations Complex Cytochrome P450 Environmental Exposure Environmental Pollutants Enzymes Epigenetic Process Epithelial Cells Etiology Event Exhibits Exposure to Flow Cytometry Gene Expression Regulation Gene Targeting Genes Genetic Genetic Transcription Human In Situ In Vitro Incidence Laboratories Ligands Link Magnetic Resonance Imaging Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Mammary Neoplasms Mammary Tumorigenesis Mammary gland Maps Mediating Mediator of activation protein Modeling Modification Molecular Mus Mutation NF-kappa B Neoplasm Metastasis Nuclear Oral Administration Outcome Pathologic Play Rattus Recruitment Activity Regulation Regulatory Element Research Project Grants Resources Risk Factors Role Signal Pathway Signal Transduction Signal Transduction Pathway Subfamily lentivirinae Testing Tissues Transgenic Mice Tumor Cell Invasion Xenograft procedure activating transcription factor aromatic hydrocarbon receptor base cancer cell cell growth cell motility cofactor environmental chemical environmental chemical exposure functional outcomes immortalized cell in vivo inhibitor/antagonist malignant breast neoplasm neoplastic cell novel promoter research study slug stable cell line transcription factor translational study tumor tumor growth tumor progression tumorigenesis

项目摘要

Known breast cancer risk factors do not completely explain the increase in breast cancer incidence in the U.S. since 1940. It has been suggested that environmental chemicals, including polycyclic aromatic hydrocarbons (PAH), have played a role in human breast cancer. PAH-induced tumorigenesis is initiated through the AhR, an evolutionary conserved transcription factor activated by ubiquitous environmental pollutants. In the original PO1, we proposed the novel hypothesis that the AhR plays an important role in malignant epithelial cell growth in part through interaction with the Wnt/CK2 and NF-xB signaling pathways. Collaborative studies with Drs. Sonenshein and Seldin have strongly supported this hypothesis and have provided new evidence suggesting an important role for the AhR in tumor progression as well. Consequently, a new hypothesis is proposed: As mammary epithelial cells progress from normal to immortalized cells and then to invasive tumors, AhR activity is modified through interactions with environmental chemicals, other transcription factors, and cofactors to differentially regulate target gene transcription and to effect changes in cell growth and invasiveness. Three aims are proposed: 1) Assess AhR-mediated tumor invasion in vitro: AhR regulation of cell invasion in 3-dimensional cultures and the potential for the AhR to influence invasiveness through modulation of Slug will be evaluated. Collaborative studies will assess the role of AhRCK2 interactions in tumor invasiveness. These mechanistic studies will provide the basis for complementary studies evaluating tumor invasion in vivo. 2) Map differential cofactor recruitment by constitutively active AhR: Studies will quantify binding of the AhR to regulatory elements within genes differentially regulated by the AhR and will reveal the spectrum of coregulators recruited by constitutively active and chemical-activated AhR in cells representing different levels of malignancy. Collaborative studies will evaluate AhR-NF-KB interactions that may influence AhR activity. 3) Define the functional consequences of constitutively active AhR in vivo: Stable cell lines in which AhR activity has been modulated (Aim 1), will be exploited in a xenograft mammary tumor model to study the role of the AhR in mammary tumor cell growth in situ. The contribution of enforced AhR expression in mammary epithelial cells also will be evaluated with MMTV-AhR transgenic mice. Evidence of AhR contributions to tumor growth and invasion provided by these studies would link environmental exposures to tumor aggressiveness and would strongly encourage translational studies with selective AhR inhibitors. New information will be obtained on AhR function in normal as compared with malignant cells, on differential control of gene transcription by the AhR, and on the molecular and functional outcomes of constitutively activated as compared with environmental chemical-activated AhR. The results will help place AhR function in the continuum of malignant transformation and will further expand on our central theme of biologically significant interactions between AhR, CK2 and NF-KB during mammary tumorigenesis.

已知的乳腺癌危险因素并不能完全解释乳腺癌发病率的增加美国自 1940 年起就已开始使用环境化学品，包括多环芳烃碳氢化合物（PAH）在人类乳腺癌中发挥了作用。 PAH 诱导的肿瘤发生开始通过 AhR，一种由普遍存在的环境激活的进化保守转录因子污染物。在最初的 PO1 中，我们提出了新的假设，即 AhR 在恶性上皮细胞的生长部分是通过与 Wnt/CK2 和 NF-xB 信号通路的相互作用来实现的。与博士的合作研究。 Sonenshein 和 Seldin 强烈支持这一假设并提供了新的证据表明 AhR 在肿瘤进展中也发挥着重要作用。最后，提出了一个新的假设：随着乳腺上皮细胞从正常细胞发展为永生化细胞，然后对于侵袭性肿瘤，AhR 活性通过与环境化学物质、其他物质的相互作用而改变转录因子和辅助因子差异调节靶基因转录并影响细胞生长和侵袭性。提出了三个目标：1) 体外评估 AhR 介导的肿瘤侵袭： AhR 对 3 维培养物中细胞侵袭的调节以及 AhR 影响的潜力将评估通过调节 Slug 的侵入性。合作研究将评估 AhRCK2 的作用肿瘤侵袭力中的相互作用。这些机制研究将为互补性研究提供基础评估肿瘤体内侵袭的研究。 2) 通过组成型活性映射差异辅因子招募 AhR：研究将量化 AhR 与受不同基因调控的基因内调控元件的结合。 AhR 并将揭示由组成型活性和化学激活招募的辅助调节器的谱细胞中的 AhR 代表不同程度的恶性肿瘤。合作研究将评估 AhR-NF-KB 可能影响 AhR 活动的相互作用。 3) 定义本构活跃的功能后果 AhR 体内：AhR 活性已被调节的稳定细胞系（目标 1）将被用于异种移植乳腺肿瘤模型研究 AhR 在乳腺肿瘤细胞原位生长中的作用。这乳腺上皮细胞中强制 AhR 表达的贡献也将通过 MMTV-AhR 进行评估转基因小鼠。这些研究提供了 AhR 对肿瘤生长和侵袭贡献的证据将环境暴露与肿瘤侵袭性联系起来，并强烈鼓励转化选择性 AhR 抑制剂的研究。正常情况下，将获得有关 AhR 功能的新信息：与恶性细胞相比，AhR 对基因转录的差异控制以及分子与环境化学激活的 AhR 相比，组成型激活的功能结果。该结果将有助于将AhR功能置于恶性转化的连续体中，并将进一步扩展关于我们的中心主题，即乳腺发育过程中 AhR、CK2 和 NF-KB 之间具有生物学意义的相互作用肿瘤发生。