Tumor tissue microRNA expression in association with triple-negative breast cancer outcomes.

Abstract

We evaluated suggested metastasis-related microRNAs (miRNAs) for their associations with disease-free survival (DFS) and overall survival (OS) of triple-negative breast cancer (TNBC). In a cohort of 456 TNBC cases, we systematically evaluated 57 previously reported metastasis-related miRNAs in tumor tissue using the NanoString nCounter assay. Cox regression was applied to evaluate miRNA expression in association with DFS and OS. In vitro assays using the TNBC cell line MDA-MB-231 were also conducted to validate epidemiological study findings. During a median follow-up of 5.3 years, 112 deaths and 97 recurrences were documented. High levels of miR-374b-5p, miR-218-5p, or miR-126-3p, or low levels of miR-27b-3p were independently associated with a favorable TNBC outcome (P < 0.01 for all). A composite score based on the levels of these four miRNAs was associated with DFS, with hazard ratios (95 % confidence interval) of 0.70 (0.43-1.15), 0.51 (0.29-0.90), and 0.18 (0.09-0.37) for the second, third, and fourth compared to the lowest quartile. Incorporating the miRNA score with known TNBC outcome predictors, i.e., age at diagnosis, tumor stage, and basal-like subtype, increased the C-index for predicting DFS from 0.68 to 0.74. Additionally, miR-126-3p was correlated with basal-like breast cancer, and miR-374b-5p modified the therapeutic effects of 5-Fluorouracil and Cyclophosphamide treatments in basal-like breast cancer patients. Restoring miR-126-3p, miR-218-5p, or miR-374b-5p, or inhibiting miR-27b-3p in MDA-MB-231 cells reduced cell proliferation. miR-374b-5p suppressed cell invasion and miR-218-5p inhibited colonization. This study provides strong evidence that the expression levels of miR-374b-5p, miR-27b-3p, miR-126-3p, and miR-218-5p in tumor tissues predict TNBC outcomes.