Akt, also known as protein kinase B (PKB), is an important protein involved in cell cycle regulation and apoptosis. Hyperactivation of the PI3K/Akt pathway can lead to cell cycle deregulation in many human cancers. We have developed transgenic mice overexpressing a wild type form of Akt (BK5.Aktwt) and a myristoylated version of the Akt (BK5.Aktmyr) under the control of the bovine keratin 5 (BK5) promoter. Overexpression of Akt in epidermis appeared to act as both an initiating and promoting stimulus in that transgenic mice developed skin tumors following initiation with DMBA only or treatment with TPA only. In addition, BK5.Aktwt transgenic mice were significantly more sensitive to two-stage carcinogenesis. BK5.Aktwt transgenic mice developed 50.4 papillomas/mouse (100% incidence) whereas the nontransgenic mice had 10.85 papillomas/mouse (100% incidence). The papillomas arising from BK5.Aktwt transgenic mice had a much shorter latency and were considerably larger than those produced in nontransgenic mice. We also obtained data to suggest that elevated Akt expression enhanced progression of papillomas to SCCs. The myristoylation sequence allows for anchorage of Akt into the cell membrane, the location of activation by PDK1. To determine the effects on tumor promotion by the constitutively active Akt transgene, a two-stage mouse skin carcinogenesis study was performed with C57BL/6 genetic background. The DMBA/TPA treated wild-type mice achieved a 22.5% tumor incidence but only a 0.46 tumor multiplicity while the DMBA/TPA treated transgenic mice obtained a 100% tumor incidence level and a tumor multiplicity of 29.8 papillomas per mouse. These results are highly significant when compared to the non-transgenic control and suggests constitutive activation of Akt acts as a strong tumor promoter. More importantly, the data suggests the ability of the Akt transgene to overcome the high resistance to tumor formation associated with the C57BL/6 background. Furthermore, the transgenic DMBA/Acetone treated mice obtained a tumor incidence of 25% and a multiplicity of 0.33, similar to the DMBA/TPA treated wild type mice. This suggests the constitutively active Akt acts as strong as the phorbol ester TPA in skin tumor promotion and can lead to tumor formation even in highly resistant models. Overall, the data presented provide further support for the hypothesis that activation of Akt plays an important role in skin tumor promotion and multistage skin carcinogenesis. Mechanisms underlying the effects of Akt during multistage skin carcinogenesis will be presented.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]