The primary goal of the research proposed in this competitive renewal application is to understand the role of Akt downstream signaling pathways in epithelial carcinogenesis. During the previous funding period, we discovered that Akt activation is an important event during the early stages of skin tumor promotion by diverse tumor promoting stimuli. Both the early and the sustained activation of Akt throughout epithelial carcinogenesis in mouse skin appear to be due primarily to activation of the EGFR. In addition, several downstream Akt targets are modulated (i.e., increased phospg the early stages of skin tumor promotion by diverse tumor promoting stimuli. Both the early and the sustained activation of Akt throughout epithelial carcinogenesis in mouse skin appear to be due primarily to activation of the EGFR. In addition, shis enhancement of susceptibility to skin tumor promotion appears to be due, in part, to modulation of certain cell cycle regulatory proteins (e.g., upregulation of cyclin D1) resulting in enhanced proliferation in response to TPA. We have also found that calorie restriction (CR) significantly reduces signaling through Akt and mTOR and reduces cyclin D1 levels both in untreated and TPA treated epidermis and this may partially explain the ability of CR to inhibit skin tumor promotion. Finally, preliminary experiments have revealed that inhibiting mTORC1 (using topical rapamycin) can block TPAinduced activation of mTORC1 signaling and epidermal hyperproliferation. In the next project period, we will test the hypothesis that enhanced Akt signaling during tumor promotion leads to increased proliferation of keratinocytes, in part, through modulation of the mTORC1 pathway leading to modulation of critical G1 to S Phase cell cycle regulatory proteins (e.g., cyclin D1). We will also test the hypothesis that activation of Akt and this specific downstream signaling pathway (i.e., mTORC1) is required for the clonal expansion of initiated bulge-region keratinocyte stem cells (KSCs) during tumor promotion. Studies will also be conducted in the context of UVB skin carcinogenesis to further demonstrate the general importance of these pathways and observations to early stages of epithelial carcinogenesis in skin.
The Specific Aims are: 1) Determine the importance of mTORC1 activation in TPA skin tumor promotion and UVB skin carcinogenesis and 2) To determine the importance of Akt1 activation specifically in bulge-region KSCs during skin carcinogenesis.
The successful completion of these studies is expected to lead to a greater understanding of the role for Akt and mTOR signaling pathways in epithelial carcinogenesis and their potential as targets for chemoprevention of cancer. Furthermore, the proposed studies will provide further evidence that KSCs, particularly those found in the bulge region of hair follicles, are the primary targets for tumor development in mouse skin.
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