Much, if not all of the biologic activity of polycyclic aromatic hydrocarbons and related pollutants (e.g. TCDD) is mediated by the aryl hydrocarbon receptor (AhR). AhR activation is associated with production of reactive metabolites, induction of proto-oncogenes, activation of transcription factors (including NF-kB), and aberrant cell function. In general, the AhR is positioned at the apex of a network of intracellular interactions which could contribute significantly to malignant transformation through multiple mechanisms. In particular, a number of recent observations suggest that the AhR is involved in regulating cell growth: (1) high level AhR expression in rodent and human tumors; (2) physical association of the AhR with RelA, an NF-kB family member; (3) up-regulation of the c-myc promoter after AhR and Re/A gene transfection; and 4) inhibition of mammary tumor cell growth with AhR antagonists and an inducible AhR antisense. From these and other results, it is hypothesized that AhR expression predisposes mammary tissue to PAH-mediated transformation and that high levels of potentially active AhR directly influence epithelial cell growth or function.
Three specific aims have been defined to test these hypotheses: (1) Evaluate AhR hyper-expression and activation during rat mammary gland tumorigenesis. These studies will determine if changes in AhR expression or function precede or coincide with malignant transformation and will provide information critical to construction of an accurate model of mammary epithelial cell transformation; (2) Generate transgenic mice in which high level AhR expression is directed toward mammary tissue. These studies will test if high level AhR expression in mammary tissue accelerates transformation and will result in the production of small animal models in which molecular mechanisms of transformation can be dissected; and (3) Determine AhR function in pre-malignant and malignant 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 or function. Proposed studies will directly address the potential role of the AhR in mammary tumorigenesis in the presence and the absence of environmental PAH.
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