SCUBE2 as a Marker of Resistance to Taxane-based Neoadjuvant Chemotherapy and a Potential Therapeutic Target in Breast Cancer.

Abstract

Taxane-based neoadjuvant chemotherapy is the most common neoadjuvant approach in breast cancer, especially in human epidermal growth factor receptor 2 (HER2)-positive and triple-negative subtypes. However, chemoresistance is a problem in many patients, and success rates are low in estrogen receptor (ER)-positive breast cancer. The aim of this study was to identify predictive markers for resistance to taxane-based therapy, which may have a potential as therapeutic targets in breast cancer. Three comprehensive breast cancer Gene Expression Omnibus datasets were analyzed to identify differentially expressed genes (DEGs) in breast cancer patients resistant to taxane-based neoadjuvant chemotherapy. Functional annotation clustering and enrichment analysis were performed on the DEGs list. A protein-protein interaction network was established with the upregulated genes. The predictive value and the differential expression of the central genes were validated in the extensive ROC Plotter database. Seventeen upregulated genes were found which were associated with resistance to taxane-based neoadjuvant therapy and high connectivity in the network analysis. ESR1, CCND1, and SCUBE2 emerged as the top three key genes associated with resistance. SCUBE2 displayed a high predictive power comparable to ESR1, and better than CCND1, the two commonly accepted markers. The predictive ability of SCUBE2 was higher in ER-positive and HER2-positive breast cancers. These results suggest that SCUBE2 may be used as a predictive marker to guide decisions on neoadjuvant therapy. Emerging evidence about the role of SCUBE2 as a coreceptor involved in tumor progression and angiogenesis also suggests SCUBE2 as a potential therapeutic target. These points should be investigated in further studies.