Alterations in mRNA profiles of trastuzumab-resistant Her-2-positive breast cancer

Abstract

Breast cancer is one of the most common malignancies in women. Neoadjuvant trastuzumab therapy improves the prognosis of certain Her-2-positive breast cancer patients, however around two-thirds of patients with Her-2-positive breast cancer do not benefit from Her-2-targeted therapy. To investigate the key mechanisms in trastuzumab resistance, potential biomarkers for neoadjuvant trastuzumab sensitivity were investigated using the gene expression omnibus (GEO) database for mRNA microarray data of Her-2-positive breast cancer patients who received neoadjuvant trastuzumab therapy. GEO profiles of 22 patients with a complete response and 48 patients with a partial response were identified in the GSE22358, GSE62327 and GSE66305 datasets. A total of 2,376, 1,000 and 1,152 differentially expressed genes in GSE22358, GSE62327 and GSE66305 datasets were demonstrated, respectively, utilizing GEO2R software. Furthermore, enriched gene ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways were analyzed using the Database for Annotation, Visualization and Integrated Discovery software. Subsequently, a protein-protein interaction network was established using STRING software. The results demonstrated that low sex-determining region Y-box 11 and high Bcl-2 expression may be employed as markers for neoadjuvant trastuzumab therapy for Her-2-positive breast cancer. More importantly, phosphoinositide 3-kinase/Akt and angiogenesis pathways, which are known to be the key targets of trastuzumab, were activated at a lower level in the partial response patients, while the Wnt and estrogen receptor signaling pathways were activated in these patients. Therefore, combination therapy of trastuzumab and anti-Wnt or hormone therapy may be a promising treatment modality and should be tested in further studies.