Data from Reduction in IκB Kinase α Expression Promotes the Development of Skin Papillomas and Carcinomas

We reported recently a marked reduction in IκB kinase α (IKKα) expression in a large proportion of human poorly differentiated squamous cell carcinomas (SCC) and the occurrence of Ikkα mutations in human SCCs. In addition, overexpression of IKKα in the epidermis inhibited the development of skin carcinomas and metastases in mice. However, whether a reduction in IKKα expression promotes skin tumor development is currently unknown. Here, we assessed the susceptibility of Ikkα hemizygotes to chemical carcinogen-induced skin carcinogenesis. Ikkα^+/− mice developed 2 times more papillomas and 11 times more carcinomas than did Ikkα^+/+ mice. The tumors were larger in Ikkα^+/− than in Ikkα^+/+ mice, but tumor latency was shorter in Ikkα^+/− than in Ikkα^+/+ mice. Some of the Ikkα^+/− papillomas and most Ikkα^+/− carcinomas lost the remaining Ikkα wild-type allele. Somatic Ikkα mutations were detected in carcinomas and papillomas. The chemical carcinogen-induced H-Ras mutations were detected in all the tumors. The phorbol ester tumor promoter induced higher mitogenic and angiogenic activities in Ikkα^+/− than in Ikkα^+/+ skin. These elevated activities were intrinsic to keratinocytes, suggesting that a reduction in IKKα expression provided a selective growth advantage, which cooperated with H-Ras mutations to promote papilloma formation. Furthermore, excessive extracellular signal-regulated kinase and IKK kinase activities were observed in carcinomas compared with those in papillomas. Thus, the combined mitogenic, angiogenic, and IKK activities might contribute to malignant conversion. Our findings provide evidence that a reduction in IKKα expression promotes the development of papillomas and carcinomas and that the integrity of the Ikkα gene is required for suppressing skin carcinogenesis. [Cancer Res 2007;67(19):9158–68]