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

Abstract

{beta}-catenin ({beta}cat) 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. {beta}cat expression is regulated by GSK-3{beta}-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 {beta}cat. In cancer cells, stabilized {beta}-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-{beta}cat (p{beta}cat) staining may be diagnostically useful in differentiating primary from metastatic melanoma. Also, a p{beta}cat peptide (residues 30-39, p33) is naturally presented by melanoma cells as a T-cell target. We evaluated the expression of pS33-{beta}cat in primary and metastatic melanoma tissues by immunohistochemistry. pS33-{beta}cat was detected in primary and metastatic melanomas and was most commonly cytoplasmic and almost never exclusively nuclear. Interestingly, staining with pS33-{beta}cat and pS33/37/T41-{beta}cat antibodies was most intense in mitotic melanoma cells, consistent with prior studies demonstrating changes in the level of {beta}cat during cell division. We observed no significant differences in p{beta}cat staining location or intensity between primary and metastatic melanomas, suggesting that p{beta}cat may have limited diagnostic or prognostic utility in melanoma. However, the high expression in dividing cells suggests promise as an immunotherapeutic target.