Abstract
BackgroundS100 family proteins have recently been identified as biomarkers in various cancers. Of this protein family, S100A14 and S100A16 are also believed to play an important role in tumor progression. The aim of the present study was to clarify the clinical significance and functional role of these molecules in breast cancer.MethodsIn a clinical study, an immunohistochemical analysis of S100A14 and S100A16 expression in archival specimens of primary tumors of 167 breast cancer patients was performed. The relationship of S100A14 and S100A16 expression to patient survival and clinicopathological variables was statistically analyzed. In an experimental study, the subcellular localization and function of these molecules was examined by using the human breast cancer cell lines MCF7 and SK-BR-3, both of which highly express S100A14 and S100A16 proteins. Cells transfected with expression vectors and siRNA for these genes were characterized using in vitro assays for cancer invasion and metastasis.ResultsImmunohistochemical analysis of 167 breast cancer cases showed strong cell membrane staining of S100A14 (53% of cases) and S100A16 (31% of cases) with a significant number of cases with co-expression (p < 0.001). Higher expression levels of these proteins were significantly associated with a younger age (<60 years), ER-negative status, HER2-positive status and a poorer prognosis. Co-expression of the two proteins showed more aggressive features with poorer prognosis. In the human breast cancer cell lines MCF7 and SK-BR-3, both proteins were colocalized on the cell membrane mainly at cell-cell attachment sites. Immunoprecipitation and immunofluorescence analyses demonstrated that the 100A14 protein can bind to actin localized on the cell membrane in a calcium-independent manner. A Boyden chamber assay showed that S100A14 and S100A16 knockdown substantially suppressed the invasive activity of both cell lines. Cell motility was also inhibited by S100A14 knockdown in a modified dual color wound-healing assay.ConclusionsTo our knowledge, this is the first report showing the correlation of expression of S100A14, S100A16, and co-expression of these proteins with poor prognosis of breast cancer patients. In addition, our findings indicate that S100A14 and S100A16 can promote invasive activity of breast cancer cells via an interaction with cytoskeletal dynamics. S100A14 and S100A16 might be prognostic biomarkers and potential therapeutic targets for breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1059-6) contains supplementary material, which is available to authorized users.
Highlights
S100 family proteins have recently been identified as biomarkers in various cancers
We have focused on the detection of novel biomarkers of cancer progression including of invasion and metastasis based on experimental studies [2] and have identified the S100 family proteins S100A14 and S100A16 as important candidate molecules for the regulation of metastatic disease
To determine the contribution of S100 protein expression to breast cancer, we first used immunohistochemistry to analyze S100A14 and S100A16 protein expression in tissue samples of 167 patients who underwent surgical resection for primary invasive breast cancer. This analysis revealed that S100A14 and S100A16 proteins were expressed mainly on the membrane of breast cancer cells, while no or faint staining was seen in normal epithelial cells of each sample (Figure 1A, representative staining)
Summary
S100 family proteins have recently been identified as biomarkers in various cancers. Of this protein family, S100A14 and S100A16 are believed to play an important role in tumor progression. The aim of the present study was to clarify the clinical significance and functional role of these molecules in breast cancer. Further understanding of the molecular mechanism of breast cancer progression would produce new biomarkers for the precise prediction of patient prognosis and for molecular targeted-therapy. We have focused on the detection of novel biomarkers of cancer progression including of invasion and metastasis based on experimental studies [2] and have identified the S100 family proteins S100A14 and S100A16 as important candidate molecules for the regulation of metastatic disease. S100 proteins have recently become of great interest because of their close association with inflammation, neurodegenerative disorders and cancer [4,5]
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