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Expression of Activated Extracellular Signal-Regulated Kinases 1/2 in Malignant Melanomas

Relationship with Clinical Outcome

Departments of Pathology [K. J., R. H., V. A. F.] and Tumor Biology [G. M. M.], Institute for Cancer Research, The Norwegian Radium Hospital, HF, Montebello, Oslo, Norway

Purpose: The purpose of the present work was to analyze the protein expression of activated extracellular signal-regulated kinases 1 and 2 (ERK1/2) in a panel of superficial spreading (SSM) and nodular (NM) primary and metastatic melanomas, and to correlate the expression level with clinicopathological parameters.

Experimental Design: Expression of activated ERK1/2 was examined by immunohistochemistry in 172 primary melanomas (108 SSM and 64 NMs), 67 metastatic lesions, and in 41 benign nevi.

Results: Fifty four percent of primary and 33% of metastatic melanomas expressed variable levels of activated ERK1/2. No immunoreactivity was detected in benign nevi. In 21% of the primaries only cytoplasmic expression was detected, whereas 3% and 30% showed positive immunoreactivity in either nucleus or cytoplasm and nucleus, respectively. Activated ERK1/2 expression varied significantly with the thickness of superficial spreading melanomas, with lower expression in thinner lesions (P = 0.016). A significant correlation between activated ERK1/2 and cyclin D1 (P = 0.031) in nodular, as well as between activated ERK1/2 and cyclin D3 (P = 0.030) in SSMs were observed. The protein level of p27^Kip1 correlated with activated ERK1/2 (P = 0.048) in the nucleus. Furthermore, a strong inverse correlation between activated ERK1/2 and membrane-bound ß-catenin (P = 0.004) in nodular melanomas was revealed. Activation of ERK1/2 did not have any impact on relapse-free or overall survival.

Conclusion: Our results suggest that activation of ERK1/2 may be involved in cell cycle regulation in SSMs. Moreover, the inverse association between membrane-bound ß-catenin and ERK1/2 in NMs suggest that ERK1/2 activation may play a role in decreasing homotypic interactions through destabilization of ß-catenin.

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