Phospho-ERK staining is a poor indicator of the mutational status of BRAF and NRAS in human melanoma.
Mutated BRAF and NRAS are suspected to contribute to melanomagenesis by activation of extracellular signal-regulated kinase (ERK). To test this notion, we analyzed the presence of phosphorylated ERK1/2 in 170 melanomas with established NRAS/BRAF mutational status and well-documented clinical follow-up by immunohistochemistry. Several notable observations were obtained: (i) phospho-ERK staining was very heterogeneous within the tumor; (ii) in most cases, ERK was phosphorylated in only a minority of tumor cells; (iii) the percentage of phospho-ERK-positive cells was not correlated with the mutational status of NRAS and/or BRAF; (iv) the Raf kinase inhibitor protein (RKIP) was expressed homogeneously in virtually all melanoma samples not reflecting the inhomogeneity of phospho-ERK; and, finally, (v) neither the portion of phospho-ERK-positive tumor cells nor the RKIP staining intensity showed any correlation to the clinical course of the patients. Furthermore, the ability of BRAF mutant melanoma cells to downregulate mitogen-activated protein kinase activation was shown in melanoma cell lines cultured at high densities or under nonadherent conditions. Our findings suggest that mitogen-activated protein kinase (MAPK) activity is subject to regulation even in BRAF/NRAS mutant melanoma cells and that high MAPK pathway signaling may be important only in distinct subsets of tumor cells.
Houben
Roland
R
Klinik für Dermatologie, Venerologie und Allergologie, Julius-Maximilians-Universität, Würzburg, Germany.
Vetter-Kauczok
Claudia S
CS
Ortmann
Sonja
S
Rapp
Ulf R
UR
Broecker
Eva B
EB
Becker
Juergen C
JC
D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D049488:Phosphatidylethanolamine Binding Protein / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D016283:Proto-Oncogene Proteins p21(ras)