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

点击翻译按钮获取中文摘要

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.