GSK3ß and cyclin D1 expression predicts outcome in early breast cancer patients.

ABSTRACT

Glycogen synthase kinase 3ß (GSK3ß) is phosphorylated and inactivated by the phosphoinositide 3 kinase PI3K/Akt pathway. Activation of Akt phosphorylates GSK3ß preventing phosphorylation of cyclin D1 which leads to accumulation and nuclear localisation of cyclin D1, activation of CDK4/6 and cell cycle progression. The CCND1 gene found at chromosome 11q13 has been shown to be amplified in approximately 15 % of breast cancers. Cyclin D1, the product of the CCND1 gene, is one of the most commonly overexpressed proteins in breast cancer. Protein expression for GSK3ß, phosphorylated-GSK3ß (p-GSK3ß), cyclin D1 and gene expression of CCND1 were examined in tissue microarrays of 1,686 patients from the Edinburgh Breast Conservation Series. High GSK3ß expression was associated with reduced distant relapse-free survival (DRFS), while no association between p-GSK3ß and breast cancer-specific survival was seen. CCND1 amplification is also associated with poor DRFS. On the contrary, cyclin D1 overexpression is associated with an increase in DRFS. Multivariate analysis was performed. We suggest that analysis of both GSK3ß and cyclin D1 expressions can be considered as a marker of good prognosis in early breast cancer.