Breast cancer is now the second most frequent cause of cancer death among women in the United States. Environmental chemical exposure and bioaccumulation throughout a women's lifetime are thought to play a substantial role in the rise in breast cancer incidence. The overarching hypothesis in our original application was that environmental carcinogens, which induce genetic and epigenetic events, set in motion interacting signaling cascades that promote a multistep process leading to mammary tumor formation. Three gene systems were the focus: the aromatic hydrocarbon receptor (AhR), the CK2 and GSK3 kinases, and the NF- ?B family of transcription factors. This paradigm-shifting model has been confirmed, and a new hypothesis on the role of these critical regulatory pathways in tumorigenesis has been developed. The investigators now propose that the interactions among these three systems play key roles at several stages of the multistep signaling process that leads to altered cell morphology and invasive tumor formation. The individual hypotheses to be tested are: Project 1: 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. New information will be obtained on AhR function in normal as compared with malignant cells, and on the molecular and functional outcomes, particularly with regard to tumor invasiveness, of constitutively active as compared with environmental chemical-activated AhR. Project 2: Upregulation of CK2 and the Wnt pathway, resulting from environmental carcinogen exposure, contributes to epithelial to mesenchymal transition (EMT), which promotes tumor cell invasion and metastasis. Targets of CK2 in this process will be identified, and the mechanism by which 7,12-dimethylbenz(a)anthracene (DMBA) interacts with CK2 in tumorigenesis and promotes CK2 upregulation will be studied. Project 3: Genetic and epigenetic events initiated by environmental carcinogen exposure induce or enhance the activity of multiple NF-?B complexes, thereby promoting a more invasive phenotype of breast cancer. In particular, studies will focus on elucidating the roles of c-Rel, RelB, and IKKe/i kinase, and tumor inhibitory effects of green tea polyphenols. Thus, this application focuses on understanding signal transduction pathways impacted by environmental carcinogen exposure, which promote neoplastic transformation, with particular emphasis on elucidating the mechanisms that influence development of invasive breast disease. The investigators will employ innovative technologies, novel in vitro model systems, transgenic mice generated in the P01, and common cell lines and reagents. These studies will provide important information on the potential link between environmental factors and critical signaling pathways in the pathogenesis of breast cancer invasion and on the targeting of these interacting signaling pathways with novel prevention or treatment modalities.
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