Abstract
Glycogen synthase kinase 3β (GSK-3β), recently found to be functionally abnormal in various types of human disease, is negatively regulated by the PI3K/Akt signaling pathway. Since Akt is constitutively activated in a subset of breast cancer, we hypothesized that GSK-3β is inappropriately inactivated in these cases. In this study, we aimed to assess (1) the overall frequency of GSK-3β inactivation in breast cancer; (2) if there is an association between Akt activation and GSK-3β inactivation; and (3) whether there is correlation between GSK-3β inactivation and various pathologic and clinical parameters. The expression of the phosphorylated form of GSK-3β (pGSK-3β) and Akt (pAkt) were used as surrogate markers of GSK-3β 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 (ER)-positive. Overall, pGSK-3β and pAkt were positive in 34 (47.2%) and 35 (48.6%) cases, respectively. These two markers were significantly correlated with each other in the overall group and in the ER-positive subgroup (p=0.01 and 0.003, Spearman, respectively). Importantly, pGSK-3β, but not pAkt, significantly correlated a worse clinical outcome in this cohort (p=0.004, Log rank). In summary, evidence of GSK-3β 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 GSK-3β inactivation confers a worse clinical outcome.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A1.
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