The primary aim of the proposed research is to determine the role of STATs, particularly STAT3, in mouse skin tumor promotion and multistage skin carcinogenesis. During the previous funding period, we found that certain STATs (signal transducers and activators of transcription) (i.e., STATs 1, 3, and 5) are activated in tumor promoter-treated epidermis, epidermis of K14.TGFalpha (transforming growth factor alpha) transgenic mice and epidermis of BK5.erbB2 transgenic mice. In addition, these same STAT family members are constitutively activated in skin papillomas generated by a DMBA-TPA two-stage carcinogenesis protocol. The mechanism for activation of STATs in both tumor promoter treated epidermis and in papillomas appears to be due to activation of the EGFr. In this revised renewal application, new preliminary data is provided using epidermis specific STAT3 deficient mice. These mice show a significantly reduced epidermal proliferative response following topical application of TPA. Thus, activation of STAT family members, and in particular STAT3, may play an important role in skin tumor promotion and multistage skin carcinogenesis. In the next funding period, we will test the hypothesis that STAT signaling, activated via EGFr/EGFr homodimers and/or EGFr/erbB2 heterodimers, is critical for the process of skin tumor promotion and for the development of autonomous growth in skin papillomas. Additionally, we will test the hypothesis that STAT3 activation mediates, in part, tumor promoter-induced epidermal hyperproliferation.
The Specific Aims are: 1) To generate transgenic mice with activated STAT3 (using a constitutively active form, STAT 3C) and examine their skin phenotype and their susceptibility to skin tumor promotion and multistage skin carcinogenesis; 2) Determine the impact of STAT3 deficiency on tumor promotion and multistage skin carcinogenesis; 3) Determine the functional consequences of STAT3 activation on proliferation/ differentiation of normal vs initiated (v-ras Ha)keratinocytes; and 4) To examine the STAT3 regulated genes in mouse epidermis contributing to skin tumor promotion and two-stage carcinogenesis. Successful completion of the studies proposed in this revised renewal application would establish STAT3 signaling as an important component of skin tumor promotion and tumor development in mouse skin. This would represent a significant advancement in our understanding of the mechanisms underlying tumor promotion by diverse agents and multistage skin carcinogenesis in general. Finally, the proposed studies could lead to the discovery of new targets for the chemoprevention of cancer.
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