QNBC Is Associated with High Genomic Instability Characterized by Copy Number Alterations and miRNA Deregulation.

Stefanne M Bortoletto,Shristi Bhattarai,Luciane R Cavalli,Aline S Fonseca,Ritu Aneja,Bruna M Sugita

doi:10.3390/ijms222111548

Abstract

Triple-negative breast cancer (TNBC) can be further classified into androgen receptor (AR)-positive TNBC and AR-negative TNBC or quadruple-negative breast cancer (QNBC). Here, we investigated genomic instability in 53 clinical cases by array-CGH and miRNA expression profiling. Immunohistochemical analysis revealed that 64% of TNBC samples lacked AR expression. This group of tumors exhibited a higher level of copy number alterations (CNAs) and a higher frequency of cases affected by CNAs than TNBCs. CNAs in genes of the chromosome instability 25 (CIN25) and centrosome amplification (CA) signatures were more frequent in the QNBCs and were similar between the groups, respectively. However, expression levels of CIN25 and CA20 genes were higher in QNBCs. miRNA profiling revealed 184 differentially expressed miRNAs between the groups. Fifteen of these miRNAs were mapped at cytobands with CNAs, of which eight (miR-1204, miR-1265, miR-1267, miR-23c, miR-548ai, miR-567, miR-613, and miR-943), and presented concordance of expression and copy number levels. Pathway enrichment analysis of these miRNAs/mRNAs pairings showed association with genomic instability, cell cycle, and DNA damage response. Furthermore, the combined expression of these eight miRNAs robustly discriminated TNBCs from QNBCs (AUC = 0.946). Altogether, our results suggest a significant loss of AR in TNBC and a profound impact in genomic instability characterized by CNAs and deregulation of miRNA expression.

Highlights

Triple-negative breast cancer (TNBC) is a highly metastatic breast cancer subtype that afflicts nearly a half million women in the US and accounts for 10–20% of newly diagnosed breast cancers worldwide [1,2]
No significant differences were observed in age, tumor grade and size, lymph node status, distant metastasis, and tumor recurrence between patients with TNBC and those with quadruple-negative breast cancer (QNBC)
The clinical heterogeneity of TNBC is evidenced by the various molecular subtypes of these tumors, as defined by gene expression patterns [9,10]

Summary

Introduction

Triple-negative breast cancer (TNBC) is a highly metastatic breast cancer subtype that afflicts nearly a half million women in the US and accounts for 10–20% of newly diagnosed breast cancers worldwide [1,2]. TNBC is predominantly diagnosed at a younger age and advanced stage [3]. It follows an aggressive clinical course with an elevated risk of relapse and metastasis, typically to visceral organs and the brain [4]. TNBC is notorious for its extensive interpatient and intratumor heterogeneity [7,8]. Based on their gene expression profiles, TNBCs can be divided into four subtypes: basal-like immune activator, basal-like immune suppressor, mesenchymal, and luminal androgen receptor (LAR) subtypes [9,10].

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