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:
    7885590
  • 负责人:
  • 金额:
    $ 27.18万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
  • 资助国家:
    美国
  • 起止时间:
  • 项目状态:
    未结题

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年以来。有人认为,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 AhR是一种进化上保守的转录因子,被普遍存在的环境因子激活, 污染物在最初的PO 1中,我们提出了新的假设,即AhR在 恶性上皮细胞生长部分通过与Wnt/CK 2和NF-xB信号通路相互作用。 Sonenshein和Seldin博士的合作研究强烈支持了这一假设, 提供了新的证据,表明AhR在肿瘤进展中也起着重要作用。因此,委员会认为, 提出了一个新的假说:随着乳腺上皮细胞从正常细胞发展为永生细胞, 然后是侵袭性肿瘤,AhR活性通过与环境化学物质的相互作用而改变, 转录因子和辅因子,以差异调节靶基因转录和影响细胞内的变化。 细胞生长和侵袭性。提出了三个目标:1)评估AhR介导的体外肿瘤侵袭: AhR在三维培养中对细胞侵袭的调节以及AhR影响细胞侵袭的潜力 将评估通过调节Slug的侵袭性。合作研究将评估AhRCK 2的作用 肿瘤侵袭性的相互作用。这些机制研究将为补充 评估体内肿瘤侵袭的研究。2)通过组成型活性的图差异辅因子募集 AhR:研究将量化AhR与差异调节基因内调节元件的结合 AhR,并将揭示由组成性活性和化学活化的 细胞中的AhR代表不同的恶性程度。合作研究将评估AhR-NF-KB 可能影响AhR活性的相互作用。3)定义组成性活跃的功能后果 体内AhR:AhR活性已被调节的稳定细胞系(目标1)将在一个新的研究中开发。 异种移植乳腺肿瘤模型,以研究AhR在乳腺肿瘤细胞原位生长中的作用。的 还将用MMTV-AhR评估乳腺上皮细胞中增强的AhR表达的贡献 转基因小鼠这些研究提供了AhR促进肿瘤生长和侵袭的证据 将环境暴露与肿瘤侵袭性联系起来,并将强烈鼓励转化 选择性AhR抑制剂的研究。将获得正常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, 与环境化学激活的AhR相比,组成性激活的AhR的功能结果。 这些结果将有助于将AhR功能置于恶性转化的连续体中,并将进一步扩大 我们的中心主题是乳腺癌发生过程中AhR、CK 2和NF-κ B之间的生物学显著相互作用, 肿瘤发生

项目成果

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会议论文数量(0)
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David H Sherr其他文献

You AhR what you eat?
你啊,你吃什么?
  • DOI:
    10.1038/ni.2213
  • 发表时间:
    2012-01-19
  • 期刊:
  • 影响因子:
    27.600
  • 作者:
    B Paige Lawrence;David H Sherr
  • 通讯作者:
    David H Sherr

David H Sherr的其他文献

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{{ truncateString('David H Sherr', 18)}}的其他基金

Endogenous and Environmental AHR Ligands in Head and Neck Cancer Aggression and Immunosuppression
头颈癌侵袭和免疫抑制中的内源性和环境 AHR 配体
  • 批准号:
    9922302
  • 财政年份:
    2019
  • 资助金额:
    $ 27.18万
  • 项目类别:
Endogenous and Environmental AHR Ligands in Head and Neck Cancer Aggression and Immunosuppression
头颈癌侵袭和免疫抑制中的内源性和环境 AHR 配体
  • 批准号:
    9752872
  • 财政年份:
    2019
  • 资助金额:
    $ 27.18万
  • 项目类别:
CHARACTERIZATION OF AHR COMPLEX IN MALIGNANT TUMOR CELLS
恶性肿瘤细胞中 AHR 复合物的表征
  • 批准号:
    8365505
  • 财政年份:
    2011
  • 资助金额:
    $ 27.18万
  • 项目类别:
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
  • 财政年份:
    2010
  • 资助金额:
    $ 27.18万
  • 项目类别:
How environmental chemicals impair immunity
环境化学物质如何损害免疫力
  • 批准号:
    7909634
  • 财政年份:
    2009
  • 资助金额:
    $ 27.18万
  • 项目类别:
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:
    7522897
  • 财政年份:
    2008
  • 资助金额:
    $ 27.18万
  • 项目类别:
High Performance Research Flow Cytometer
高性能研究流式细胞仪
  • 批准号:
    7217177
  • 财政年份:
    2007
  • 资助金额:
    $ 27.18万
  • 项目类别:
CHARACTERIZATION OF AHR COMPLEX IN MALIGNANT TUMOR CELLS
恶性肿瘤细胞中 AHR 复合物的表征
  • 批准号:
    6978482
  • 财政年份:
    2004
  • 资助金额:
    $ 27.18万
  • 项目类别:
AH RECEPTOR/TRANSCRIPTION FACTOR AS A REGULATOR OF HYDROCARBON BIOACTIVITY
AH 受体/转录因子作为碳氢化合物生物活性的调节剂
  • 批准号:
    6578799
  • 财政年份:
    2002
  • 资助金额:
    $ 27.18万
  • 项目类别:
Novel strategy for AL amyloid immunotherapy
AL 淀粉样蛋白免疫治疗的新策略
  • 批准号:
    6590088
  • 财政年份:
    2002
  • 资助金额:
    $ 27.18万
  • 项目类别:
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