GSK3β and cyclin D1 expression predicts outcome in early breast cancer patients

Abstract

Glycogen synthase kinase 3β (GSK3β) is phosphorylated and inactivated by the phosphoinositide 3 kinase PI3K/Akt pathway. Activation of Akt phosphorylates GSK3β 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 GSK3β, phosphorylated-GSK3β (p-GSK3β), cyclin D1 and gene expression of CCND1 were examined in tissue microarrays of 1,686 patients from the Edinburgh Breast Conservation Series. High GSK3β expression was associated with reduced distant relapse-free survival (DRFS), while no association between p-GSK3β 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 GSK3β and cyclin D1 expressions can be considered as a marker of good prognosis in early breast cancer.

GSK-3 inhibition overcomes chemoresistance in human breast cancer

“…Recently, GSK-3β has been credentialed as a potential therapeutic target in human breast cancer [23,24]. GSK-3β knockdown significantly inhibited breast cancer cell proliferation whereas GSK-3α knockdown had only a minor effect in four breast cancer cell lines, providing further support for GSK-3βas a breast cancer therapeutic target [24].…”

“…Previously, we identified GSK-3β as a novel therapeutic target in human leukemia, pancreatic, colon, bladder and renal cancer [11,14–17]. In human breast carcinoma, it has been shown that overexpression of GSK-3β was associated with several indicators of poor prognosis and breast cancer patients with GSK-3β expression in the highest quartile (246 of 1686 cases) had a 2.7 and 1.7-fold increased risk of distant relapse 5 and 10 years after tumor resection, respectively [23]. A recent study demonstrated that GSK-3β knockdown significantly inhibited breast cancer cell proliferation whereas GSK-3α knockdown had only a minor effect in four breast cancer cell lines further credentialing GSK-3β as a viable therapeutic target for the treatment of breast cancer [24].…”

High interstitial fluid pressure promotes tumor cell proliferation and invasion in oral squamous cell carcinoma

“…Heat shock protein (HSP)A4, also known as HSP70, has been shown to be significantly associated with low differentiation and poor prognosis in a number of malignant tumors (17)(18)(19). CCND1, also known as cyclin D1, is overexpressed in several human tumors; its expression is induced by growth factors and occurs at multiple levels, including increased transcription, translation and protein stability (20)(21)(22). Cyclin D1 plays an important role in G1 phase transition, which is a kinase-independent function, by sequestering cyclin-dependent kinase (CDK) inhibitors, such as CDKN1A (p21) and CDKN1B (p27) for the efficient activation of CDK2-containing complexes (23,24).…”

The Akt/mTOR Pathway and Estrogen Receptor Phosphorylations : a crosstalk with potential to predict tamoxifen resistance in breast cancer

“…Although the CCND1 gene has been suggested as a driver of the amplicon, more data is still needed to reveal its role in the amplicon [58]. Amplification of 11q13 and the individual gene CCND1 in breast cancer has been described as markers of poor prognosis [59,60]. The 11q13 amplicon is not restricted to breast cancer, but also found in other cancer diseases such as ovarian, and head and neck carcinoma, and reported to show decreased disease-free survival [61,62].…”

“…The prognostic value of cyclin D1 in breast cancer has been debated. Some studies show that high cyclin D1 indicated improved prognosis in non-selected breast cancer and in ER-positive endocrine treated breast cancer patients [59,60,78]. Other studies have found opposing data, showing poor prognosis with high cyclin D1 mRNA expression in ER-positive, but not in ER-negative breast cancer [69], and high cyclin D1 protein expression predicted worse outcome in early stage, ER-positive, endocrine treated patients [79].…”