Abstract P4-07-13: High microRNA-621 level predicts a better response to neoadjuvant chemotherapy in breast cancer patients

Abstract

Abstract Purpose: Weekly paclitaxel plus carboplatin (PCb) regimen is an effective neoadjuvant chemotherapy for breast cancer. However, some patients respond to this regimen poorly and suffer from side effects. In this study, we aimed to define the microRNA (miRNA) biomarker for predicting sensitivity to PCb chemotherapy in breast cancer patients, and to explore the potential molecular mechanisms. Experimental Design: 81 patients with stages II and III breast cancer, who received four cycles of weekly PCb regimen preoperative chemotherapy, were included. Gene expression profiles from 31 patients was used as training set to determine differentially expressed genes (DEGs) and to predict miRNAs that may be associated with chemotherapeutic sensitivity. The other 50 patients were analyzed as validation set to test the accuracy of DEG identification and miRNAs prediction by quantitative real-time PCR. In parallel, in vitro and in vivo analyses were carried out to determine the potential mechanisms of miRNA-dependent drug sensitivity. Results: Gene profiling analyses in the training set revealed significant correlation between high expression level of miR-345 and miR-621 and pathologic complete response (pCR) in breast cancer patients. We further validated that the expression level of miR-621 was significantly higher in tumor tissues of pCR patients than that in non-pCR patients (P = 0.01). In breast cancer cell lines, ectopic overexpression of miR-621 promoted apoptosis and increased chemosensitivity to paclitaxel and carboplatin both in vitro and in vivo. The potential miR-621-target genes were determined by TargetScan and miRNA CLIP-seq database, which were further confirmed as DEGs reversely-correlated to miR-621 in breast cancer patient samples. Among those, FBXO11 was verified as one of the direct targets of miR-621 in breast cancer cells, whose expression level negatively associated with chemosensitivity in breast cancer patients. The molecular mechanisms by which miR-621/FBXO11 axis regulates chemosensitivity may involve regulation of p53 transcriptional activity and epithelial-mesenchymal transition (EMT) in breast cancer cells. Conclusions: Our study revealed a strong correlation between miR-621 expression and chemosensitivity in breast cancers. High level of miR-621 predicts sensitivity to PCb regimen neoadjuvant chemotherapy in breast cancer patients who tend to achieve pCR. The increased chemosensitivity may be mediated by down-regulation of FBXO11 gene, which leads to enhanced p53 transactivity and reduced EMT in breast cancer cells. Therefore, miR-621 may be used as predictive biomarker and the potential therapeutic target in breast cancer treatment. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-07-13.