Non-melanoma skin cancer (NMSC) includes basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), which together are the most common type of human malignancy. More than one million Americans develop one or more of these tumors annually and BCCs represent more than 75% of NMSC. Thus BCCs are a major public health problem and a major cause of morbidity and escalating health care costs in this country. Environmental exposure to solar ultraviolet B (UVB) is the major risk factor for the induction of BCCs. The molecular basis underlying the development of these tumors is now known to relate to mutations in the hedgehog signaling pathway including patched (PTCH). sonic hedgehog (SHH) and smoothened (SMO). In addition, an animal model for BCCs. the patched heterozygous knockout mouse, has been developed which provides a system with which to explore the molecular pathogenesis of UVB-induced BCCs. It is known that skin exposure to UVB drives a proliferative stimulus to epidermal keratinocytes and that induction of the enzyme ornithine decarhoxylase (ODC') is a major contributor to the augmented growth and clonal expansion of initiated cells. UVB exposure also enhances oxidant stress in the skin. which is accompanied by increased generation of reactive oxygen species (ROS) that can induce ODC and augment keratinocyte proliferation. In this proposal we will test the hypothesis that factors which enhance cell proliferation such as increased ODC expression and oxidant stress are crucial for UVB induction of BCCs. We have developed a novel modification of patch +/- heterozygous mice in which ODC is overexpressed (ptch +I-/ODC TgN). These mice have accelerated spontaneous development of microscopic BCCs like tumors by the age of 20 weeks and with UVB exposure visible BCCs within 30 weeks. We will utilize this animal model to probe the pathogenesis of IJVB-induced BCCs by assessing the role of over-expression of ODC, by evaluating the effects of altered cell cycle regulation and by measuring oxidant stress. The result of these studies will be used to devise innovative pharmacogenetic approaches to the chemoprevention of UVB-induced BCCs. It is likely that novel anti-carcinogenic agents potentially suitable for testing in the human population could be identified as a result of the studies in this proposal.
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