The long-term goal of this project is to understand how apoptosis influences the development of non-melanoma skin cancer. Keratinocyte apoptosis mediated by p53 is thought to represent an important defense against cutaneous squamous cell carcinoma (SCC), although the role of apoptosis resistance in tumor development has not been well established. Our initial work has focused on survivin, a newly identified apoptosis inhibitor, that is absent in normal keratinocytes but expressed in SCC and precursor lesions. Our hypothesis is that survivin expression is important in the development of SCC. To investigate the role of survivin in skin carcinogenesis, we have generated a transgenic mouse (K14-survivin) expressing survivin in the skin. Before moving to molecular analyses of survivin function in skin cancer, we will first use this transgenic system to investigate the role of survivin in well-characterized models of skin tumor formation. Preliminary studies suggest that survivin expression may oppose the p53-apoptotic pathway in keratinocytes, and is important for preventing papilloma regression and promoting progression to SCC. First, we will determine if survivin expression combined with loss of p53 enhances SCC formation by subjecting K14-survivin mice on a p53+/- background to chemical carcinogenesis. Second, we will examine whether survivin expression controls tumor formation at the level of papilloma regression, and if it can serve as a tumor initiator or promoter in this system. Third, the effect of transgenic survivin expression on ultraviolet-B (UVB)-induced tumor formation will be investigated using K14-survivin mice on a hairless background. Finally, we will explore a mechanistic basis for the effect of transgenic survivin on UVB-induced carcinogenesis by correlating tumor formation and regression with the development and growth of p53-mutated keratinocyte clones. These proposed studies promise to elucidate the role of survivin in the development of SCC, and validate this molecule as a potential new therapeutic target in skin cancer.
| Raj, Deepak; Brash, Douglas E; Grossman, Douglas (2006) Keratinocyte apoptosis in epidermal development and disease. J Invest Dermatol 126:243-57 |
| Zhang, Wengeng; Hanks, Adrianne N; Boucher, Kenneth et al. (2005) UVB-induced apoptosis drives clonal expansion during skin tumor development. Carcinogenesis 26:249-57 |
| Brash, Douglas E; Zhang, Wengeng; Grossman, Douglas et al. (2005) Colonization of adjacent stem cell compartments by mutant keratinocytes. Semin Cancer Biol 15:97-102 |
| Bowen, Anneli R; Hanks, Adrianne N; Murphy, Kelley J et al. (2004) Proliferation, apoptosis, and survivin expression in keratinocytic neoplasms and hyperplasias. Am J Dermatopathol 26:177-81 |
| Allen, Sarah M; Florell, Scott R; Hanks, Adrianne N et al. (2003) Survivin expression in mouse skin prevents papilloma regression and promotes chemical-induced tumor progression. Cancer Res 63:567-72 |
