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.

Public Health Relevance

The successful completion of these studies is expected to lead to a greater understanding of the role for specific Akt 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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Molecular Oncogenesis Study Section (MONC)
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Blair, Donald G
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University of Texas Austin
Schools of Pharmacy
United States
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Rho, Okkyung; Kiguchi, Kaoru; Jiang, Guiyu et al. (2014) Impact of mTORC1 inhibition on keratinocyte proliferation during skin tumor promotion in wild-type and BK5.AktWT mice. Mol Carcinog 53:871-82
Checkley, L Allyson; Rho, Okkyung; Angel, Joe M et al. (2014) Metformin inhibits skin tumor promotion in overweight and obese mice. Cancer Prev Res (Phila) 7:54-64
Hursting, Stephen D; Digiovanni, John; Dannenberg, Andrew J et al. (2012) Obesity, energy balance, and cancer: new opportunities for prevention. Cancer Prev Res (Phila) 5:1260-72
Carr, Theresa D; DiGiovanni, John; Lynch, Christopher J et al. (2012) Inhibition of mTOR suppresses UVB-induced keratinocyte proliferation and survival. Cancer Prev Res (Phila) 5:1394-404
Rho, Okkyung; Kim, Dae Joon; Kiguchi, Karou et al. (2011) Growth factor signaling pathways as targets for prevention of epithelial carcinogenesis. Mol Carcinog 50:264-79
Checkley, L Allyson; Rho, Okkyung; Moore, Tricia et al. (2011) Rapamycin is a potent inhibitor of skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate. Cancer Prev Res (Phila) 4:1011-20
Kiguchi, Kaoru; Kitamura, Takuya; Moore, Tricia et al. (2010) Dual inhibition of both the epidermal growth factor receptor and erbB2 effectively inhibits the promotion of skin tumors during two-stage carcinogenesis. Cancer Prev Res (Phila) 3:940-52
Moral, Marta; Segrelles, Carmen; Lara, M Fernanda et al. (2009) Akt activation synergizes with Trp53 loss in oral epithelium to produce a novel mouse model for head and neck squamous cell carcinoma. Cancer Res 69:1099-108
Hursting, Stephen D; Perkins, Susan N; Lavigne, Jackie A et al. (2009) Urothelial overexpression of insulin-like growth factor-1 increases susceptibility to p-cresidine-induced bladder carcinogenesis in transgenic mice. Mol Carcinog 48:671-7
Moral, Marta; Segrelles, Carmen; Martínez-Cruz, Ana Belén et al. (2009) Transgenic mice expressing constitutively active Akt in oral epithelium validate KLFA as a potential biomarker of head and neck squamous cell carcinoma. In Vivo 23:653-60

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