MicroRNA-regulated protein-protein interaction networks and their functions in breast cancer

Abstract

MicroRNAs, which are small endogenous RNA regulators, have been associated with various types of cancer. Breast cancer is a major health threat for women worldwide. Many miRNAs were reported to be associated with the progression and carcinogenesis of breast cancer. In this study, we aimed to discover novel breast cancer-related miRNAs and to elucidate their functions. First, we identified confident miRNA-target pairs by combining data from miRNA target prediction databases and expression profiles of miRNA and mRNA. Then, miRNA-regulated protein interaction networks (PINs) were constructed with confident pairs and known interaction data in the human protein reference database (HPRD). Finally, the functions of miRNA-regulated PINs were elucidated by functional enrichment analysis. From the results, we identified some previously reported breast cancer-related miRNAs and functions of the PINs, e.g., miR-125b, miR-125a, miR-21, and miR-497. Some novel miRNAs without known association to breast cancer were also found, and the putative functions of their PINs were also elucidated. These include miR-139 and miR-383. Furthermore, we validated our results by receiver operating characteristic (ROC) curve analysis using our miRNA expression profile data, gene expression-based outcome for breast cancer online (GOBO) survival analysis, and a literature search. Our results may provide new insights for research in breast cancer-associated miRNAs.

Figure 1

Analysis flow chart used in this work. After expression profiles and target prediction databases were fetched and preprocessed, they were subjected to the analysis process described here and in the “Experimental Section”.

Figure 2

Receiver operating characteristic (ROC) curve of let-7c from our miRNA array dataset. For ROC curves of other miRNAs, see Figure S1.

Figure 3

The let-7c-regulated protein interaction network (PIN). This is one of the 18 miRNA-regulated PINs constructed in this work. Figures of all other miRNA-regulated PINs are displayed in Supplementary Figures S2–S13.

Figure 4

Validation of let-7c result. Gene expression-based outcome for breast cancer online (GOBO) survival analysis of let-7c-regulated PIN members marked with the following functions: (A) Microtubule cytoskeleton; (B) Negative regulation of programmed cell death; and (C) negative regulation of cell death. Red: samples with high expression of selected gene set (PIN members); grey: samples with low expression of selected gene set (PIN members).