COBRE: CREIGHTON: PILOT 3:ERBB2& UV IRRADIATION IN SKIN CARCINOGENESIS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The research described in this proposal is designed to characterize the role of erbB2 in the response of the skin to ultraviolet radiation (UV). erbB receptor tyrosine kinases, including the orphan receptor erbB2, are known to regulated a variety of processes in the skin. Preliminary data have shown that abrogation of erbB2 results in: (1) decreased proliferation and a G2/M-phase cell cycle arrest in keratinocytes, (2) increased apoptosis in cultured keratinocytes and in the skin, and (3) increased UV-induced apoptosis. We propose that erbB2 is an important negative regulator of the protective response of keratinocytes. Characterizing the role of erbB2 in the skin's response to UV-exposure is especially important due to the fact that UV (in the form of sunlight) is known to cause non-melanoma skin cancer, the most common cancer in the United States. UV is a complete carcinogen, causing DNA damage as well as promoting the clonal expansion of DNA-damaged cells to form tumors. Since overexpression of erbB2 results in spontaneous skin tumor formation while abrogation of the erbB2 signaling partner EGFR (epidermal growth factor receptor) decreases skin tumor growth, we propose that erbB2 promotes the growth of UVR-induced skin tumors. Utilizing erbB2 null and wild type keratinocytes and skin grafting protocols, we plan to test our hypothesis that erbB2 regulates the response of the skin to UV and contributes to UV-induced skin carcinogenesis. Furthermore, these investigations will determine whether modulation of erbB2 signaling is an appropriate target for skin cancer prevention or treatment. The Specific Aims include 1) determining the mechanisms by which erbB2 influences the response of keratinocytes to UV and 2) measuring the extent to which erbB2 increases UV-induced skin tumor growth from initiated keratinocytes.