MiRNA expression patterns in normal breast tissue and invasive breast cancers of BRCA1 and BRCA2 germ-line mutation carriers.

Shoko Vos,Venu Raman,Paul J Van Diest,Farhad Vesuna,Petra Van Der Groep

doi:10.18632/oncotarget.5617

Abstract

miRNA deregulation has been found to promote carcinogenesis. Little is known about miRNA deregulation in hereditary breast tumors as no miRNA expression profiling studies have been performed in normal breast tissue of BRCA1 and BRCA2 mutation carriers. miRNA profiles of 17 BRCA1- and 9 BRCA2-associated breast carcinomas were analyzed using microarrays. Normal breast tissues from BRCA1 and BRCA2 mutation carriers (both n = 5) and non-mutation carriers (n = 10) were also included. Candidate miRNAs were validated by qRT-PCR. Breast carcinomas showed extensive miRNA alteration compared to normal breast tissues in BRCA1 and BRCA2 mutation carriers. Moreover, normal breast tissue from BRCA1 mutation carriers already showed miRNA alterations compared to non-mutation carriers. Chromosomal distribution analysis showed several hotspots containing down- or up-regulated miRNAs. Pathway analysis yielded many similarities between the BRCA1 and BRCA2 axes with miRNAs involved in cell cycle regulation, proliferation and apoptosis. Lesser known pathways were also affected, including cellular movement and protein trafficking. This study provides a comprehensive insight into the potential role of miRNA deregulation in BRCA1/2-associated breast carcinogenesis. The observed extensive miRNA deregulation is likely the result of genome-wide effects of chromosomal instability caused by impaired BRCA1 or BRCA2 function. This study's results also suggest the existence of common pathways driving breast carcinogenesis in both BRCA1 and BRCA2 germ-line mutation carriers.

Highlights

Breast cancer, the most common cancer as well as the leading cause of death in women worldwide [1, 2], can occur both in sporadic and hereditary settings
The patient samples consisted of 5 classes: BRCA1-associated breast carcinomas (BRCA1-C) (n = 17); BRCA2-associated breast carcinomas (BRCA2-C) (n = 9); normal breast tissue from BRCA1 germ-line mutation carriers (BRCA1-N) (n = 5) and BRCA2 germ-line mutation carriers (BRCA2-N) (n = 5), both derived from prophylactic mastectomies; and normal breast tissue from non-mutation carriers derived from mammoplasty specimens (n = 10)
MiRNA expression profiles were investigated by miRNA microarray between normal and cancer tissue from BRCA1 and BRCA2 germ-line mutation carriers, in comparison with normal tissue from non-carriers

Summary

Introduction

The most common cancer as well as the leading cause of death in women worldwide [1, 2], can occur both in sporadic and hereditary settings. Germ-line mutations in the BRCA1 or BRCA2 genes are the most common causes of breast cancer predisposition resulting in a 70% and 60% lifetime risk of developing breast cancer, respectively [3, 4]. MiRNA expression patterns can predict therapy response and resistance [25] These findings suggest that deregulated miRNA expression is important in sporadic breast carcinogenesis. The aims of this study were: (1) to analyze differences in miRNA expression profiles between BRCA1/2-associated breast carcinomas, normal breast tissue from BRCA1 and BRCA2 germline mutation carriers, and normal breast tissue from non-mutation carriers; (2) to obtain more insight into BRCA1/2-associated carcinogenesis by identification of target genes and pathways regulated by miRNAs

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