Mechanisms of PAH-Induced Mammary Tumorigenesis

描述(摘自申请人的摘要)：芳烃 受体(AhR)是PER/Arnt/Sim转录家族中的一员 调节多种细胞功能的因子。从历史上看， AHR的功能已在其激活的背景下进行了评估 环境化学品，如多环芳烃(PAH)。这些 将AhR激活与反应性代谢物产生联系起来的研究， 原癌基因诱导，其他转录因子的诱导，以及 细胞生长异常。最近的研究有力地表明，AHR可以是 在没有外源配体的情况下具有结构性活性。一个后果是 这种激活被认为是细胞生长的失调。除其他外， 结果：这一假说得到了以下支持：1)核局部化和高密度 AhR在啮齿动物和人类肿瘤中的水平表达，2)物理联系 AhR与调节原癌基因的NF-kB家族成员RelA的关系 转录，3)c-myc启动子和c-Myc蛋白表达上调 AHR和REIA基因在乳腺肿瘤细胞系中的转染及4)抑制作用 AhR拮抗剂和诱导型AhR对人乳腺肿瘤细胞生长的影响 反义cdna。因此，这个项目的中心假设是 乳腺肿瘤中高水平的潜在活性AhR会影响细胞生长。 已经定义了两个具体的目标来检验这些假设：1.生成 将AhR高水平表达导向乳腺的转基因小鼠 组织。对这些小鼠的研究将确定AhR在上皮细胞中的作用 体内细胞转化和正常乳腺发育。 此外，生产的小鼠将促进定义分子的研究 在存在和潜在地不存在的情况下的转变机制 外源AhR配体。2.测定变形人乳房的AhR功能 癌细胞系。除了将结果扩展到人类系统之外，这些 研究将阐明推测ahr的分子机制。 来影响细胞的生长。将特别强调潜力 AhR信号通路与细胞周期蛋白调控的相互作用 Rb、核因子-kB和c-Myc以及乳腺AhR复合体的组成 肿瘤。

DESCRIPTION (Adopted from the Applicant's Abstract): The aryl hydrocarbon receptor (AhR) is a member of the growing family of Per/ARNT /Sim transcription factors which modulate a wide variety of cellular functions. Historically, the function of the AhR has been evaluated in the context of its activation by environmental chemicals such as polycyclic aromatic hydrocarbons (PAH). These studies associate AhR activation with reactive metabolite production, proto-oncogene induction, induction of other transcription factors, and aberrant cell growth. More recent studies strongly suggest that the AhR can be constitutively active in the absence of exogenous ligands. A consequence of this activation is postulated to be dysregulation of cell growth. Among other results, this hypothesis is supported by: 1) nuclear localization and high level expression of the AhR in rodent and human tumors, 2) physical association of the AhR with RelA, an NF-kB family member which regulates proto-oncogene transcription, 3) up-regulation of the c-myc promoter and c-Myc protein after AhR and ReIA gene transfection in mammary tumor cell lines, and 4) inhibition of human mammary tumor cell growth with AhR antagonists and inducible AhR antisense cDNA. Accordingly, the central hypothesis of this project is that high levels of potentially active AhR in mammary tumors influences cell growth. Two specific aims have been defined to test these hypotheses: 1. Generate transgenic mice in which high level AhR expression is directed to mammary tissue. Studies with these mice will define the role of the AhR in epithelial cell transformation in vivo and in normal mammary gland development. Furthermore, the mice produced will facilitate studies defining the molecular mechanisms of transformation in the presence and, potentially, the absence of exogenous AhR ligands. 2. Determine AhR function in transformed human breast cancer cell lines. In addition to extending results to human systems, these studies will elucidate molecular mechanisms through which the AhR is postulated to influence cell growth. Particular emphasis will be place on potential interactions between the AhR signaling pathway and regulation of cell cyclins, Rb, NF-KB, and c-Myc, and on the composition of the AhR complex in mammary tumors.