Role of AhR/Arnt Signaling Pathway in Carcinogenesis

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DESCRIPTION (provided by applicant): Malignant melanoma is on the rise in industrialized nations. Indeed, the incidence of mortality related to melanoma has increased by 34% in the United States from 1973-1992. However, there are few effective treatments developed for melanoma. We propose that the aryl hydrocarbon receptor (AhR) pathway plays a role in melanoma progression through the activation of matrix remodeling enzymes. We have chosen to use 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as the agent to activate the AhR- pathway. TCDD and related polycyclic and halogenated aromatic hydrocarbons (PAH/HAH) are ubiquitous environmental contaminants that are the unintentional by-products of industrial combustion. TCDD is ideal for examination of the AhR pathway in melanoma for three reasons: (1.) skin is a target tissue for TCDD-activation of the AhR pathway; (2.) and TCDD is not metabolized; and (3) TCDD is non-mutagenic, and therefore the effects we observe should be directly related to activation of the AhR pathway. We hypothesize that TCDD-activation of the AhR/Arnt pathway stimulates melanoma progression by altering expression of the genes involved in matrix remodeling, specifically the matrix metalloproteinases (MMPs). MMP activity is necessary for cell migration through matrix barriers, and expression of these enzymes correlates with aggressive and invasive tumors. Our preliminary data in melanoma cells demonstrate that both non-invasive and invasive melanoma lines are responsive to TCDD, and invasive melanoma cells express MMPs in response to TCDD exposure. Further, we also show increased invasiveness of melanoma cells when treated with TCDD. This suggests that TCDD directly increases melanoma invasion by activating matrix degradation. Therefore, the specific aims for this proposal are: (1.) Elucidate the molecular mechanism mediating TCDD-induced expression of MMPs in melanoma cell lines. (2.) Elucidate the role of the AhR in TCDD-induced changes in MMP expression in melanoma. (3.) Demonstrate the role of the AhR pathway in melanoma migration and invasion using an in vitro invasion assay. (4.) Using a three-dimensional skin model system, determine the role of cell-cell interaction on AhR-activation of MMP expression.