J. S. Young1, T. Kawaguchi1, L. Yan2, Q. Qi2, S. Liu2, K. Takabe1 1Roswell Park Cancer Institute,Department Of Surgical Oncology,Buffalo, NEW YORK, USA 2Roswell Park Cancer Institute,Department Of Biostatistics And Bioinformatics,Buffalo, NEW YORK, USA
Introduction: MicroRNAs (miRNAs) are short (19-25 nucleotides) noncoding RNAs, which have been discovered to exert function through the degradation or inhibition of mRNA translation. Dysregulation of miRNAs has been identified to play a critical role in carcinogenesis and breast cancer progression. Some miRNAs are reported to be associated with drug sensitivity, while others are associated with drug resistance. In this study, several miRNAs known to be related to the sensitivity or resistance of different breast cancer drug treatments were evaluated for association with overall survival using The Cancer Genome Atlas (TCGA). This included miR-221/222 related to tamoxifen (TAM), miR-30a related to Taxol/doxorubicin (TAX/DOX), miR-210 related to trastuzumab, miR-342 related to tamoxifen, miR-328 related to mitoxantrone, miR-326 related to VP-16/doxorubicin/MIT, miR-487a related to MIT, and miR-31 related to staurosporine/DOX.
Methods: All clinical datasets were obtained from The Cancer Genome Atlas (TCGA). MiRNA-seq data were retrieved from the GDC data portal to evaluate known drug resistance or sensitivity-related miRNAs (miR-221/222, miR-30a, miR-210, miR-342, miR-328, miR-326, miR-487a, and miR-31) and correlate them clinically to survival. Patients were separated into groups based on high and low expression of miRNA-specific thresholds and survival plots were generated using a Cox proportional hazard model.
Results: Among the 1097 breast cancer cases logged in TCGA, 1053 cases were found to contain appropriate data for analysis. Patients with high expression levels of miR-342, reported to be related to TAM sensitivity, have increased overall survival (p=0.035). Patients with high expression levels of miR-30a, reported to be associated with TAX/DOX sensitivity, have significant increased overall survival (p=0.032). Patients with high expression levels of miR-31, reported to be associated with staurosporine/DOX sensitivity, have significant increased overall survival (p=0.038) as well. However, miR-328, miR-326, miR-487a, and miR-210 have previously been reported to have some association with increased response to chemotherapy. In our analysis using TCGA data, they did not show any significant association with overall survival. Surprisingly, high expression levels of miR-221 and miR-222, thought to be related to TAM resistance, demonstrated significant increased overall survival (p=0.047, 0.032, respectively).
Conclusion: Although the role of miRNAs is important in drug sensitivity and resistance, its impact on survival should be validated using large clinical databases such as TCGA.