Melanoma is a common disease that is frequently lethal. About 50,000 new cases and 8,000 melanoma-related deaths will occur in the US in 2004. Early metastases are characteristic of melanoma and are an ominous sign, as current therapeutic interventions have little effect on survival. The lack of accurate prognostic indicators and effective therapies emphasize the need for a better understanding of the genetic and phenotypic changes in melanoma formation and progression. Activating mutations in BRAF occur in about 70% of melanomas and melanocytic nevi and implicate MAP kinase pathway signaling in melanoma. A subset of familial and sporadic melanomas have mutations involving the CDKN2A locus encoding the overlapping tumor suppressor genes p16INK4A and p14ARF. The observation that activating mutations in beta-catenin occur at a low but reproducible rate raises the possibility that constitutive WNT pathway signaling may result in melanoma. This hypothesis is supported by features of WNT pathway activation in roughly 40% of melanomas in the absence of activating beta-catenin mutations. Our goal is to evaluate the role of beta-catenin activation in benign melanocytes and on melanoma formation in mice. These studies will rely on conditional activation of beta-catenin using Cre-lox recombination and will utilize a new mouse strain expressing a tamoxifen-inducible form of Cre specifically in melanocytes that we have generated and characterized. We will utilize this mouse model to functionally evaluate the effects of melanocyte-specific activatior of beta-catenin on: 1). melanocyte proliferation, differentiation, and migration in vitro and in vivo 2). melanoma formation in conjunction with Cdnk2a loss, Pten loss or Hras activation and 3). melanoma progression to metastasis Additionally, we will determine: the relationship between melanocyte stem cells and melanoma forfnation, the replicative potential of melanocytes outside of the stem cell niche, and will examine beta-catenin signaling targets in human melanoma using a 400 sample tissue microarray.
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