Mechanisms of PAH-Induced Mammary Tumorigenesis

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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.