Abstract 1077: Dominant negative PI3-Kinase inhibits UV-induced squamous cell carcinoma in vivo.

Phosphoinositide-3 Kinase (PI3-Kinase) is an upstream regulator of cellular proliferation and anti-apoptotic signaling that has been implicated in cancer induction in many tissues, including skin. Pharmacological inhibition of PI3-Kinase is effective at inhibiting both chemical and UV-driven skin carcinogenesis. However, the specificity of these pharmacological inhibitors is often questioned. Therefore, specific genetic inhibition of PI3-Kinase in the epidermis needs to be carried out in mice. We report here on the generation of a new transgenic mouse which constitutively expresses the dominant negative mutant form of the regulatory subunit of the PI3-Kinase dimer, p85, in the epidermis under control of the keratin-5 promoter. These p85DN transgenic mice were derived on the SKH-1 hairless genetic background. A chronic UVB exposure experiment showed significant inhibition of both tumor size (p=0.0012) and tumor burden (p=0.0003) for mice carrying the transgene compared to wildtype littermates. The time to first tumor was also delayed in transgenic mice, but with only marginal significance (p=0.07). p85DN mice also showed significant inhibition of epidermal Activator Protein-1 (AP-1) transcription factor activity after acute UVB treatment (p=0.046). UVB induced activation of AP-1 in the epidermis has been shown to play a functional role in UVB mouse skin carcinogenesis. Further analysis of protein expression after acute treatment with UVB suggests that Akt signaling and COX-2 activation are both downregulated in p85DN transgenic mice. To our knowledge, this is the first report of genetic inhibition of PI3-Kinase in mouse skin carcinogenesis studies. Together, these data suggest a functional role of PI3-Kinase in UVB-induced squamous cell carcinoma and support the assertion that inhibition of this pathway is beneficial in chemoprevention of non-melanoma skin cancer. This work was supported in part by the following NIH grants: K07CA132956, K07CA132956-02S1, P01CA27502 and P30CA23074. Citation Format: Sally E. Dickinson, Erik R. Olson, Jadrian J. Rusche, P. Jane Criswell, Jack Zhang, Zagong Dong, Chengcheng Hu, Kathylynn Saboda, David S. Alberts, G. Timothy Bowden. Dominant negative PI3-Kinase inhibits UV-induced squamous cell carcinoma in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1077. doi:10.1158/1538-7445.AM2013-1077