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Selective Role for Mek1 but not Mek2 in the Induction of Epidermal Neoplasia

¹ Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California; ² Veterans Affairs Palo Alto Healthcare System, Palo Alto, California; ³ Department of Dermatology, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan; and ⁴ Centre de Recherche en Cancérologie de l'Université Laval, CHUQ, Hotel-Dieu de Québec, Quebec, Canada

Requests for reprints: Paul A. Khavari, Program in Epithelial Biology, Stanford University School of Medicine, 269 Campus Drive, Room 2145, Stanford, CA 94305. Phone: 650-725-5266; Fax: 650-723-8762; E-mail: khavari{at}stanford.edu.

Key Words: MAP kinase • Mek • Erk • cancer • skin

The Ras/Raf/Mek/Erk mitogen-activated protein kinase pathway regulates fundamental processes in normal and malignant cells, including proliferation, differentiation, and cell survival. Mutations in this pathway have been associated with carcinogenesis and developmental disorders, making Mek1 and Mek2 prime therapeutic targets. In this study, we examined the requirement for Mek1 and Mek2 in skin neoplasia using the two-step 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA) skin carcinogenesis model. Mice lacking epidermal Mek1 protein develop fewer papillomas than both wild-type and Mek2-null mice following DMBA/TPA treatment. Mek1 knockout mice had smaller papillomas, delayed tumor onset, and half the tumor burden of wild-type mice. Loss of one Mek1 allele, however, did not affect tumor development, indicating that one Mek1 allele is sufficient for normal papilloma formation. No difference in TPA-induced hyperproliferation, inflammation, or Erk activation was observed between wild-type, conditional Mek1 knockout, and Mek2-null mice, indicating that Mek1 findings were not due to a general failure of these processes. These data show that Mek1 is important for skin tumor development and that Mek2 cannot compensate for the loss of Mek1 function in this setting. [Cancer Res 2009;69(9):3772–8]