Phospho-β-catenin expression in primary and metastatic melanomas and in tumor-free visceral tissues

Abstract

Abstractβ-catenin (βcat) is an important downstream effector in the Wnt signaling pathway and plays an important role in the development and progression of many cancers including melanoma. βcat expression is regulated by GSK-3β-mediated phosphorylation at positions 33, 37 and 41. In normal cells, phosphorylation at these sites triggers proteasomal degradation, which in turn prevents accumulation of free cytoplasmic βcat. In cancer cells, stabilized β-catenin translocates into the nucleus, where it associates with TCF/Lef proteins to activate transcription of genes that promote tumorigenesis and metastasis. It has been suggested that nuclear phospho-βcat (pβcat) staining may be diagnostically useful in differentiating primary from metastatic melanoma. Also, a pβcat peptide (residues 30-39, p33) is naturally presented by melanoma cells as a T-cell target. We evaluated the expression of pS33-βcat in primary and metastatic melanoma tissues by immunohistochemistry. pS33-βcat was detected in primary and metastatic melanomas and was most commonly cytoplasmic and almost never exclusively nuclear. Interestingly, staining with pS33-βcat and pS33/37/T41-βcat antibodies was most intense in mitotic melanoma cells, consistent with prior studies demonstrating changes in the level of βcat during cell division. We observed no significant differences in pβcat staining location or intensity between primary and metastatic melanomas, suggesting that pβcat may have limited diagnostic or prognostic utility in melanoma. However, the high expression in dividing cells suggests promise as an immunotherapeutic target.