Model-Based Integration Analysis Revealed Presence of Novel Prognostic miRNA Targets and Important Cancer Driver Genes in Triple-Negative Breast Cancers.

Masood Zaka,Savas Konur,Chris W Sutton,Yonghong Peng

doi:10.3390/cancers12030632

Abstract

Background: miRNAs (microRNAs) play a key role in triple-negative breast cancer (TNBC) progression, and its heterogeneity at the expression, pathological and clinical levels. Stratification of breast cancer subtypes on the basis of genomics and transcriptomics profiling, along with the known biomarkers’ receptor status, has revealed the existence of subgroups known to have diverse clinical outcomes. Recently, several studies have analysed expression profiles of matched mRNA and miRNA to investigate the underlying heterogeneity of TNBC and the potential role of miRNA as a biomarker within cancers. However, the miRNA-mRNA regulatory network within TNBC has yet to be understood. Results and Findings: We performed model-based integrated analysis of miRNA and mRNA expression profiles on breast cancer, primarily focusing on triple-negative, to identify subtype-specific signatures involved in oncogenic pathways and their potential role in patient survival outcome. Using univariate and multivariate Cox analysis, we identified 25 unique miRNAs associated with the prognosis of overall survival (OS) and distant metastases-free survival (DMFS) with “risky” and “protective” outcomes. The association of these prognostic miRNAs with subtype-specific mRNA genes was established to investigate their potential regulatory role in the canonical pathways using anti-correlation analysis. The analysis showed that miRNAs contribute to the positive regulation of known breast cancer driver genes as well as the activation of respective oncogenic pathway during disease formation. Further analysis on the “risk associated” miRNAs group revealed significant regulation of critical pathways such as cell growth, voltage-gated ion channel function, ion transport and cell-to-cell signalling. Conclusion: The study findings provide new insights into the potential role of miRNAs in TNBC disease progression through the activation of key oncogenic pathways. The results showed previously unreported subtype-specific prognostic miRNAs associated with clinical outcome that may be used for further clinical evaluation.

Highlights

Triple-negative breast cancer (TNBC) is a heterogeneous group of cancers defined by lack of expression of estrogen receptor (Er), progesterone receptor (Pr) and human epidermal growth factorCancers 2020, 12, 632; doi:10.3390/cancers12030632 www.mdpi.com/journal/cancers receptor2 (Her2) [1,2]
With distant relapse-free survival (DRFS), whereas the miRNA signature showed a broad lack of reproducibility (p-value = 0.13) with over 80% overlap with the Bockhorn dataset when assessed for overall survival (Figures S7 and S8)
Some of the prognostic miRNAs observed in this study are somehow linked to various cancers, but this is the first time that we have identified triple-negative breast cancer (TNBC) subtype-specific miRNAs associated with overall survival (OS) and distant metastases-free survival (DMFS) survival

Summary

Introduction

Triple-negative breast cancer (TNBC) is a heterogeneous group of cancers defined by lack of expression of estrogen receptor (Er), progesterone receptor (Pr) and human epidermal growth factorCancers 2020, 12, 632; doi:10.3390/cancers12030632 www.mdpi.com/journal/cancers receptor (Her2) [1,2]. Several studies have analysed expression profiles of matched mRNA and miRNA to investigate the underlying heterogeneity of TNBC and the potential role of miRNA as a biomarker within cancers. Results and Findings: We performed model-based integrated analysis of miRNA and mRNA expression profiles on breast cancer, primarily focusing on triple-negative, to identify subtype-specific signatures involved in oncogenic pathways and their potential role in patient survival outcome. Using univariate and multivariate Cox analysis, we identified 25 unique miRNAs associated with the prognosis of overall survival (OS) and distant metastases-free survival (DMFS) with “risky” and “protective” outcomes The association of these prognostic miRNAs with subtype-specific mRNA genes was established to investigate their potential regulatory role in the canonical pathways using anti-correlation analysis. The results showed previously unreported subtype-specific prognostic miRNAs associated with clinical outcome that may be used for further clinical evaluation

Methods

Findings

Discussion

Conclusion