Evidence of antagonistic predictive effects of miRNAs in breast cancer cohorts through data-driven networks

Abstract

AbstractNon-coding micro RNAs (miRNAs) dysregulation seems to play an important role in the pathways involved in breast cancer occurrence and progression. In different studies, opposite functions may be assigned to the same miRNA, either promoting the disease or protecting from it. Our research tackles the following issues: (i) why aren’t there any concordant findings in many research studies regarding the role of miRNAs in the progression of breast cancer? (ii) could a miRNA have either an activating effect or an inhibiting one in cancer progression according to the other miRNAs with which it interacts? For this purpose, we analyse the AHUS dataset made available on the ArrayExpress platform by Haakensen et al. The breast tissue specimens were collected over 7 years between 2003 and 2009. miRNA-expression profiling was obtained for 55 invasive carcinomas and 70 normal breast tissue samples. Our statistical analysis is based on a recently developed model and feature selection technique which, instead of selecting a single model (i.e. a unique combination of miRNAs), delivers a set of models with equivalent predictive capabilities that allows to interpret and visualize the interaction of these features. As a result, we discover a set of 112 indistinguishable models (in a predictive sense) each with 4 or 5 miRNAs. Within this set, by comparing the model coefficients, we are able to identify three classes of miRNA: (i) oncogenic miRNAs; (ii) protective miRNAs; (iii) undefined miRNAs which can play both an oncogenic and a protective role according to the network with which they interact. These results shed new light on the biological action of miRNAs in breast cancer and may contribute to explain why, in some cases, different studies attribute opposite functions to the same miRNA.