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

已知的乳腺癌危险因素不能完全解释#年乳腺癌发病率增加的原因。 自1940年以来一直是美国。有人建议，包括多环芳烃在内的环境化学品 碳氢化合物(PAH)在人类乳腺癌中发挥了作用。启动多环芳烃诱导的肿瘤形成 通过AhR，一个由无处不在的环境激活的进化保守的转录因子 污染物。在最初的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信号通路的相互作用来实现。 与Sonenshein博士和Seldin博士的合作研究有力地支持了这一假设，并 提供了新的证据，表明AhR在肿瘤进展中也发挥了重要作用。因此， 提出了一种新的假说：随着乳腺上皮细胞从正常向永生化细胞的发展， 然后到侵袭性肿瘤，AhR的活性通过与环境化学物质的相互作用而改变，其他 转录因子和辅因子，以不同的方式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)评估AhR介导的肿瘤体外侵袭： AHR对三维培养细胞侵袭的调节及AhR的潜在影响 将评估通过调节段塞来进行的侵入性。合作研究将评估AhRCK2的作用 肿瘤侵袭性中的相互作用。这些机制研究将为补充 评估肿瘤体内侵袭性的研究。2)构型活跃的差异性辅因子招募图 AHR：研究将量化AhR与差异调控基因内调控元件的结合 AhR和将揭示由成分活性和化学激活招募的协同调节子的光谱 代表不同恶性程度的细胞中的AHR。合作研究将评估AhR-NF-KB 可能影响AhR活性的相互作用。3)界定构成活动的功能后果 体内AHR：在其中AhR活性已被调节的稳定细胞系(Aim 1)，将在一个 建立异种乳腺肿瘤模型，研究AhR在乳腺肿瘤细胞原位生长中的作用。这个 MMTV-AhR也将评估乳腺上皮细胞AhR表达增强的作用 转基因小鼠。这些研究提供了AhR对肿瘤生长和侵袭的贡献的证据 将环境暴露与肿瘤侵袭性联系起来，并强烈鼓励 选择性AhR抑制剂的研究。在正常AS中将获得有关AhR函数的新信息 与恶性肿瘤细胞相比，在AhR对基因转录的差异调控上，在分子水平上 与环境化学激活的AhR相比，成分激活的AhR的功能结果。 这一结果将有助于将AhR功能置于恶性转化的连续体中，并将进一步扩展 关于AhR、CK2和NF-KB在乳腺过程中具有重要生物学意义的相互作用的中心主题 肿瘤发生学。

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.