APPLICANT'S DESCRIPTION Breast cancer is now the second most frequent cause of death among women in the United States. To improve prevention and treatment modalities for this disease, one needs to understand the pathogenesis of breast cancer, including both environmental and genetic factors. This Program Project is based upon the hypothesis that the development and progression of breast cancer is a multistage process associated with molecular changes that result in cells acquiring malignant and then invasive and metastatic potential. In this application, pathways in this multistep signaling process leading to mammary tumor formation will be elucidated. In particular, the roles of three gene systems that functionally interact will be determined: the aromatic hydrocarbon receptor, the CK2 and GSK3 kinases and the wnt signaling pathway, and the NF-kB/Rel family of factors. Project 1 will evaluate the role of the aromatic hydrocarbon receptor/transcription factor (AhR) in the development of mammary tumors and examine factors controlling AhR expression and function in signaling, including interaction with the RelA subunit of NF-kB. Project 2 will pursue studies on the regulatory serine threonine kinases casein kinase II (CK2), and glycogen synthase kinase 3 (GSK3) and their roles in the wnt signaling pathway and in mammary development and transformation. Project 3 will characterize the aberrant expression of NF-kB/Rel transcription factors, and the role of kinases such as CK2, and elucidate the functional role of NF-kB activation in mammary tumor progression. All of these projects will make use of common model systems including carcinogen-treated rats, trangenic mouse models for hypothesis testing in whole animals, and human breast cancer tissue specimens for correlation with human disease. The results of these studies will provide important information on the potential link between environmental factors and increased incidence of breast cancer, on the roles of these critical signaling pathways in the pathogenesis of breast cancer, and on their use as biomarkers or potential therapeutic targets in novel treatment modalities.