Clinical and biological significance of GSK-3β inactivation in breast cancer-an immunohistochemical study

Glycogen synthase kinase 3 beta, recently found to be functionally abnormal in various types of human disease, is negatively regulated by the PI3K/Akt signaling pathway As Akt is constitutively activated in a subset of breast cancer, we hypothesized that glycogen synthase kinase 3 beta is inappropriately inactivated in these cases In this study, we aimed to assess (1) the overall frequency of glycogen synthase kinase 3 beta inactivation in breast cancer, (2) whether there is an association between Akt activation and glycogen synthase kinase 3 beta inactivation, and (3) whether there is a correlation between glycogen synthase kinase 3 beta inactivation and various pathologic and clinical parameters The phosphorylated form of glycogen synthase kinase 3 beta (pGSK-3 beta) and Akt (pAkt) were used as surrogate markers for glycogen synthase kinase 3 beta inactivation and Akt activation, respectively Immunohistochemistry applied to paraffin-embedded tissues was used to assess 72 consecutive invasive mammary carcinomas, of which 50 were estrogen receptor-positive Overall, pGSK-3 beta and pAkt were positive in 34 (47 2%) and 35 (48 6%) cases, respectively These 2 markers were significantly correlated with each other in the overall group and in the estrogen receptor positive subgroup (P = 01 and 003, Spearman, respectively) Importantly, pGSK-3 beta, but not pAkt, significantly correlated a worse clinical outcome in this cohort (P = 004, log rank) In summary, evidence of glycogen synthase kinase 3 beta inactivation was found in approximately half of the invasive mammary carcinomas Our data suggest that this abnormality is likely attributed to Akt activation and that glycogen synthase kinase 3 beta inactivation confers a worse clinical outcome (C) 2010 Elsevier Inc All rights reserved