The long-term aim of this project is to understand how sunlight causes skin cancer. Skin is a unique system for revealing early events in cancer because the lesions are observable, the carcinogen is known, and some cancers progress through defined stages. We initially focussed on UV-induced mutations. Now, we are focussing on UV-induced apoptosis and its role in preventing or accelerating sunlight-induced cancer. The working hypothesis is that a key step in developing skin precancers is loss of cellular proofreading. That is, abnormal cells no longer commit suicide. Our previous work generated a model at each of three levels: genes, cell populations, and pharmacologic agents. Genetic model: Apoptosis requires both an abnormality detector, which involves p53, and a cell cycle abnormality signal. Cell population model: A UV-induced p53 mutation renders a cell apoptosis-resistant. Additional UV allows the mutant cell to clonally expand at the expense of its normal neighbors, resulting in a precancer. Pharmacology model: Many drugs affect the abnormality detector or the abnormality signal. The altered apoptosis biases the competition between normal and mutant cell populations, so that these agents act as chemopreventives or tumor promoters. The research in this application uses cultured cells, mouse skin, and human skin to test individual points of these models: i) Does apoptosis- resistance enable a mutant cell to clonally expand to a precancerous lesion? ii) Do the different mutant p53 alleles found in human skin cancers and precancers have different phenotypes for apoptosis versus cell cycle arrest? iii) Do chemopreventive agents and tumor promoters act by influencing UV-induced cellular proofreading? iv) What genes influence UV-induced cellular proofreading? v) How does a DNA photoproduct signal cell cycle arrest or apoptosis? vi) Does p53- mediated clonal expansion clone out single mutant cells already present in sun-damaged skin? These studies could find that: sunlight acts as a tumor promoter by killing unmutated cells; chemoprevention is beneficial only before apoptosis-resistant cells appear; and the genomic location of a DNA photoproduct determines whether cell cycle arrest or apoptosis ensues. The questions addressed here are directly relevant to the health of an increasing number of individuals: skin cancers are now as frequent as all other cancers combined. More broadly, the mechanisms operating in keratinocytes are likely to be a part of cancer development in other cell types as well.
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