Abstract
To understand the mechanism underlying metastasis, identification of a mechanism-based and common biomarker for circulating tumour cells (CTCs) in heterogenous breast cancer is needed. SET, an endogenous inhibitor of protein phosphatase 2A, was overexpressed in all subtypes of invasive breast carcinoma tissues. Treatment with SET-targeted siRNAs reduced the motility of MCF-7 and MDA-MB-231 cells in transwell assay. SET knockdown reduced the number of mammospheres by 60–70% in MCF-7 and MDA-MB-231 cells, which was associated with the downregulation of OCT4 and SLUG. Hence, we analysed the presence of SET-expressing CTCs (SET-CTCs) in 24 breast cancer patients. CTCs were enriched using a size-based method and then immunocytochemically analysed using an anti-SET antibody. SET-CTCs were detected in 6/6 (100%) patients with recurrent breast cancer with a median value of 12 (12 cells/3 mL blood), and in 13/18 (72.2%) patients with stage I–III breast cancer with a median value of 2.5, while the median value of healthy controls was 0. Importantly, high numbers of SET-CTCs were correlated with lymph node metastasis in patients with stage I–III disease. Our results indicate that SET contributes to breast cancer progression and can act as a potential biomarker of CTCs for the detection of metastasis.
Highlights
Breast cancer is a heterogeneous disease classified into four clinical subtypes based on the expression of hormone receptors (HR), including oestrogen and progesterone receptors (ER/PR) and human epidermal growth factor receptor 2 (HER2)[1]
As many cancer cells lose epithelial features due to epithelial-mesenchymal transition (EMT) during metastasis[6,7], identification of a new molecule that plays a key role in metastasis and that is expressed in circulating tumour cells (CTCs) is necessary
SET is a 39-kDa oncoprotein encoded by the set gene, which was discovered as a component of a set-can fusion gene in acute myeloid leukemia (AML)[8]
Summary
Breast cancer is a heterogeneous disease classified into four clinical subtypes based on the expression of hormone receptors (HR), including oestrogen and progesterone receptors (ER/PR) and human epidermal growth factor receptor 2 (HER2)[1]. As well as the development of new mechanism-based agents, is important for overcoming metastatic disease. To achieve this goal, a comprehensive understanding of the characteristics of primary tumours and cancer cells in circulation, called circulating tumour cells (CTCs), is critical, as CTCs are believed to be “seeds” of metastasis[2,3]. PP2A is a major serine/threonine phosphatase regulating multiple signalling pathways, including those involved in cell proliferation and metastasis, which antagonises kinase activities[11]. We hypothesised that SET might be the desired target molecule, if it is expressed in CTCs. In this study, we found that SET was overexpressed in breast cancer tissues of all subtypes. The results presented here indicate that the oncoprotein SET is a useful biomarker for detecting CTCs, irrespective of EMT status, which may be beneficial for breast cancer treatment
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