Integrated analysis reveals microRNA networks coordinately expressed with key proteins in breast cancer.

Miriam Ragle Aure,Prahlad Ram,Gordon B Mills,Eldri U Due,Kristine Kleivi Sahlberg,Sandra Jernström,Hans Kristian Moen Vollan,Yiling Lu,Vessela N Kristensen,Marit Krohn,Ole Christian Lingjærde,Rolf Kåresen,Anne-Lise Børresen-Dale,Einar Rødland

doi:10.1186/s13073-015-0135-5

Abstract

BackgroundThe role played by microRNAs in the deregulation of protein expression in breast cancer is only partly understood. To gain insight, the combined effect of microRNA and mRNA expression on protein expression was investigated in three independent data sets.MethodsProtein expression was modeled as a multilinear function of powers of mRNA and microRNA expression. The model was first applied to mRNA and protein expression for 105 selected cancer-associated genes and to genome-wide microRNA expression from 283 breast tumors. The model considered both the effect of one microRNA at a time and all microRNAs combined. In the latter case the Lasso penalized regression method was applied to detect the simultaneous effect of multiple microRNAs.ResultsAn interactome map for breast cancer representing all direct and indirect associations between the expression of microRNAs and proteins was derived. A pattern of extensive coordination between microRNA and protein expression in breast cancer emerges, with multiple clusters of microRNAs being associated with multiple clusters of proteins. Results were subsequently validated in two independent breast cancer data sets. A number of the microRNA-protein associations were functionally validated in a breast cancer cell line.ConclusionsA comprehensive map is derived for the co-expression in breast cancer of microRNAs and 105 proteins with known roles in cancer, after filtering out the in-cis effect of mRNA expression. The analysis suggests that group action by several microRNAs to deregulate the expression of proteins is a common modus operandi in breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-015-0135-5) contains supplementary material, which is available to authorized users.

Highlights

The role played by microRNAs in the deregulation of protein expression in breast cancer is only partly understood
The mRNA-protein relationship The correlation between mRNA expression and protein expression in the primary Oslo2 data set ranged from −0.19 (KRAS) to 0.87 (ERBB2, ESR1, PGR, and AR) (Table 1)
Examples of low- and high-correlation relationships and dependence between protein expression and expression subtype for some breast cancer-associated proteins are shown in Figure 1, while the scatterplots of all 105 mRNA-protein relationships are given in Additional file 6

Summary

Introduction

The role played by microRNAs in the deregulation of protein expression in breast cancer is only partly understood. Since the initial discovery of microRNAs (miRNAs) as post-trancriptional regulators of gene expression, a complex network of coordinate regulatory interactions between miRNAs and mRNAs has been unravelled (see, for example, [1]). Network focused studies have emphasized the interplay between miRNAs and transcription factors and have revealed how miRNAs play pivotal regulatory roles in disease-specific subnetworks such as those found in breast cancer [9]. Direct and indirect effects of miRNAs can involve joint regulation of multiple genes by a single miRNA species and joint regulation of a single gene by multiple miRNAs. The importance of mapping such relationships is suggested by studies showing that miRNAs can have a relatively weak regulatory effect on individual proteins [10,11], and at the same time a strong effect on the pathway activation level by coordinately targeting multiple genes in the same pathway [12]

Objectives

Methods

Results

Discussion

Conclusion