A novel panel of differentially-expressed microRNAs in breast cancer brain metastasis may predict patient survival

Athina Giannoudis,Carlo Palmieri,Francesco Falciani,Angela Platt-Higgins,Mosavar Farahani,Leonie S Young,Philip S Rudland,Katherine A Brougham,Damir Varešlija,Kim Clarke,Michael D Jenkinson,Lucille Rainbow,Rasheed Zakaria,Stuart Ruthven

doi:10.1038/s41598-019-55084-z

Abstract

Breast cancer brain metastasis (BCBM) is an area of unmet clinical need. MicroRNAs (miRNAs) have been linked to the metastatic process in breast cancer (BC). In this study, we aim to determine differentially-expressed miRNAs utilising primary BCs that did not relapse (BCNR, n = 12), primaries that relapsed (BCR) and their paired (n = 40 pairs) brain metastases (BM) using the NanoString™ nCounter™ miRNA Expression Assays. Significance analysis of microarrays identified 58 and 11 differentially-expressed miRNAs between BCNR vs BCR and BCR vs BM respectively and pathway analysis revealed enrichment for genes involved in invasion and metastasis. Four miRNAs, miR-132-3p, miR-199a-5p, miR-150-5p and miR-155-5p, were differentially-expressed within both cohorts (BCNR-BCR, BCR-BM) and receiver-operating characteristic curve analysis (p = 0.00137) and Kaplan-Meier survival method (p = 0.0029, brain metastasis-free survival; p = 0.0007, overall survival) demonstrated their potential use as prognostic markers. Ingenuity pathway enrichment linked them to the MET oncogene, and the cMET protein was overexpressed in the BCR (p < 0.0001) and BM (p = 0.0008) cases, compared to the BCNRs. The 4-miRNAs panel identified in this study could be potentially used to distinguish BC patients with an increased risk of developing BCBM and provide potential novel therapeutic targets, whereas cMET-targeting warrants further investigation in the treatment of BCBM.

Highlights

Www.nature.com/scientificreports and TPM1 tumour-suppressor genes, whereas it affects metastasis by directly targeting TIMP3, SERPIN5B, PDCD4 and BCL28,9
We investigated the differential-expression of miRNAs between primary BC samples that did not recur (BCNR) vs primary BC samples that recur (BCR) and primary BCR vs their paired brain metastases (BM)
Assessment of the global variation using principal component analysis (PCA) indicated a molecular distinction between the primary BCNR, the BCRs that progress to brain metastasis and the BCBM cases

Summary

Introduction

Www.nature.com/scientificreports and TPM1 tumour-suppressor genes, whereas it affects metastasis by directly targeting TIMP3, SERPIN5B, PDCD4 and BCL28,9. Only three studies with very limited numbers of samples (n = 4–9), have compared miRNA expression between matched primary unselected BC and BCBM tissues[12,13,14]. The current study screened a larger cohort of unselected BC samples that recur (BCR) and their paired brain metastases (BM), as well as primary BC samples that did not recur (BCNR) to identify differentially-expressed miRNAs related to BCBM.

Objectives

Methods

Results

Conclusion