An Integrated In Silico, In Vitro and Tumor Tissues Study Identified Selenoprotein S (SELENOS) and Valosin-Containing Protein (VCP/p97) as Novel Potential Associated Prognostic Biomarkers in Triple Negative Breast Cancer

Simple Summary Triple negative breast cancer (TNBC) represents a clinical challenge because its early relapse, poor overall survival and lack of effective treatments. Altered levels selenoproteins have been correlated with development and progression of some cancers, however, no consistent data are available about their involvement in TNBC. Here we analyzed the expression profile of all twenty-five human selenoproteins in TNBC cells and tissues by a systematic approach, integrating in silico and wet lab approaches. We showed that the expression profiles of five selenoproteins are specifically dysregulated in TNBC. Most importantly, by a bioinformatics analysis, we selected selenoprotein S and its interacting protein valosin-containing protein (VCP/p97) as inter-related with the others and whose coordinated over-expression is associated with poor prognosis in TNBC. Overall, we highlighted two mechanistically related novel proteins whose correlated expression could be exploited for a better definition of prognosis as well as suggested as novel therapeutic target in TNBC. Background. Triple negative breast cancer (TNBC) is a heterogeneous group of tumors with early relapse, poor overall survival, and lack of effective treatments. Hence, new prognostic biomarkers and therapeutic targets are needed. Methods. The expression profile of all twenty-five human selenoproteins was analyzed in TNBC by a systematic approach.In silicoanalysis was performed on publicly available mRNA expression datasets (Cancer Cell Line Encyclopedia, CCLE and Library of Integrated Network-based Cellular Signatures, LINCS). Reverse transcription quantitative PCR analysis evaluated selenoprotein mRNA expression in TNBC versus non-TNBC and normal breast cells, and in TNBC tissues versus normal counterparts. Immunohistochemistry was employed to study selenoproteins in TNBC tissues. STRING and Cytoscape tools were used for functional and network analysis. Results.GPX1, GPX4, SELENOS, TXNRD1 and TXNRD3 were specifically overexpressed in TNBC cells, tissues and CCLE/LINCS datasets. Network analysis demonstrated that SELENOS-binding valosin-containing protein (VCP/p97) played a critical hub role in the TNBCselenoproteins sub-network, being directly associated with SELENOS expression. The combined overexpression of SELENOS and VCP/p97 correlated with advanced stages and poor prognosis in TNBC tissues and the TCGA dataset. Conclusion. Combined evaluation of SELENOS and VCP/p97 might represent a novel potential prognostic signature and a therapeutic target to be exploited in TNBC.

Automated summary

In this study, the expression profiles of twenty-five human selenoproteins in triple negative breast cancer (TNBC) were analyzed. It was found that five selenoproteins were specifically dysregulated in TNBC. Additionally, selenoprotein S and its interacting protein valosin-containing protein (VCP/p97) were identified as mechanistically related proteins whose coordinated over-expression was associated with poor prognosis in TNBC.