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Lack of Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase Signaling Shows a New Type of Melanoma

¹ Departments of Biochemistry and Biophysics, Pharmacology, Dermatology, Pathology and Laboratory Medicine, Cell Biology, Medicine and Genetics, The Lineberger Comprehensive Cancer Center, The Center for Environmental Health and Susceptibility, University of North Carolina School of Medicine, Chapel Hill, North Carolina; ² Department of Pathology, Yale University School of Medicine, New Haven, Connecticut; ³ Department of Cancer Biology, M. D. Anderson Cancer Center, Houston, Texas; ⁴ Department of Dermatology, Emory University, Atlanta, Georgia; and ⁵ Department of Dermatology, University of Rochester, Rochester, New York

Requests for reprints: Norman E. Sharpless, The Lineberger Cancer Center, CB# 7295, Departments of Medicine and Genetics, The University of North Carolina School of Medicine, Chapel Hill, NC 27599-7295. Phone: 919-966-1185 (office), 919-966-4067 (laboratory); Fax: 919-966-8212; E-mail: nes{at}med.unc.edu.

The majority of human melanomas harbor activating mutations of either N-RAS or its downstream effector B-RAF, which cause activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase and the ERK MAPK cascade. The melanoma-relevant effectors of ERK activation, however, are largely unknown. In this work, we show that increased ERK activation correlates strongly with mutational status of N-RAS or B-RAF in 21 melanoma cell lines. Melanoma lines that were wild-type for RAS/RAF showed low levels of ERK activation comparable with primary human melanocytes. Through supervised analysis of RNA expression profiles, we identified 82 genes, including TWIST1, HIF1, and IL-8, which correlated with ERK activation across the panel of cell lines and which decreased with pharmacologic inhibition of ERK activity, suggesting that they are ERK transcriptional targets in melanoma. Additionally, lines lacking mutations of N-RAS and B-RAF were molecularly distinct and characterized by p53 inactivation, reduced ERK activity, and increased expression of epithelial markers. Analysis of primary human melanomas by tissue microarray confirmed a high correlation among expression of these epithelial markers in a heterogeneous sample of 570 primary human tumors, suggesting that a significant frequency of primary melanomas is of this "epithelial-like" subtype. These results show a molecularly distinct melanoma subtype that does not require ERK activation or epithelial-mesenchymal transformation for progression. [Cancer Res 2007;67(4):1502–12]

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