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

• 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
• 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; 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

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不能完全解释乳腺癌发病率的增加 自1940年以来，美国。有人建议环境化学物质，包括多环芳族 碳氢化合物（PAH）在人类乳腺癌中发挥了作用。 PAH诱导的肿瘤发生启动 通过AHR，无处不在的环境激活的进化保守转录因子 污染物。在原始的PO1中，我们提出了一个新的假设，即AHR在 恶性上皮细胞的生长部分通过与Wnt/CK2和NF-XB信号通路相互作用。 与博士的合作研究。 Sonenshein和Seldin强烈支持这一假设，并具有 提供了新的证据，表明AHR在肿瘤进展中也起着重要作用。最后， 提出了一个新的假设：随着乳腺上皮细胞从正常到永生的细胞和 然后是浸润性肿瘤，通过与环境化学物质的相互作用来改变AHR活性 转录因子和辅助因子以差异调节靶基因转录，并​​影响变化 细胞生长和侵入性。提出了三个目的：1）评估体外AHR介导的肿瘤侵袭： AHR调节三维培养物中的细胞侵袭，以及AHR影响的潜力 通过调节SLUG的侵入性将得到评估。协作研究将评估AHRCK2的作用 肿瘤侵入性的相互作用。这些机械研究将为互补提供基础 研究评估体内肿瘤侵袭的研究。 2）通过组成型活动地绘制差异辅助因子募集 AHR：研究将量化AHR与受差异化调节基因调节元件的结合 AHR并将揭示由组成型活性和化学激活募集的核心测量剂的光谱 代表不同水平恶性肿瘤的细胞中的AHR。协作研究将评估AHR-NF-KB 可能影响AHR活性的相互作用。 3）定义组成性活动的功能后果 AHR体内：稳定的细胞系已调节AHR活性（AIM 1），将在A中利用 异种移植乳腺肿瘤模型研究AHR在原位乳腺肿瘤细胞生长中的作用。这 还将用MMTV-AHR评估乳腺上皮细胞中强制AHR表达的贡献 转基因小鼠。 AHR对这些研究提供的肿瘤生长和侵袭的贡献的证据 将环境暴露与肿瘤的侵略性联系起来，并强烈鼓励翻译 选择性AHR抑制剂的研究。将在正常的AHR功能上获得新信息 与恶性细胞相比，在AHR对基因转录的差异控制下，在分子上 与环境化学化学激活的AHR相比，组成型激活的功能结果。 结果将有助于将AHR功能放在恶性转化的连续性中，并将进一步扩展 关于我们在乳腺期间AHR，CK2和NF-KB之间生物学上具有重要意义相互作用的中心主题 肿瘤发生。