TGFbeta and miRNA regulation in familial and sporadic breast cancer.

Katia Danza,Rosamaria Pinto,Rosanna Lacalamita,Stefania Tommasi,Simona De Summa,Ondina Popescu,Massimo Carella,Brunella Pilato,Maria Digennaro,Orazio Palumbo

doi:10.18632/oncotarget.14899

Abstract

The term ‘BRCAness’ was introduced to identify sporadic malignant tumors sharing characteristics similar to those germline BRCA-related. Among all mechanisms attributable to BRCA1 expression silencing, a major role has been assigned to microRNAs. MicroRNAs role in familial and sporadic breast cancer has been explored but few data are available about microRNAs involvement in homologous recombination repair control in these breast cancer subgroups. Our aim was to seek microRNAs associated to pathways underlying DNA repair dysfunction in breast cancer according to a family history of the disease. Affymetrix GeneChip microRNA Arrays were used to perform microRNA expression analysis in familial and sporadic breast cancer. Pathway enrichment analysis and microRNA target prediction was carried out using DIANA miRPath v.3 web-based computational tool and miRWalk v.2 database. We analyzed an external gene expression dataset (E-GEOD-49481), including both familial and sporadic breast cancers. For microRNA validation, an independent set of 19 familial and 10 sporadic breast cancers was used. Microarray analysis identified a signature of 28 deregulated miRNAs. For our validation analyses by real time PCR, we focused on miR-92a-1*, miR-1184 and miR-943 because associated to TGF-β signalling pathway, ATM and BRCA1 genes expression. Our results highlighted alterations in miR-92a-1*, miR-1184 and miR-943 expression levels suggesting their involvement in repair of DNA double-strand breaks through TGF-beta pathway control.

Highlights

Breast cancer (BC) is a complex disease characterized by high level of heterogeneity, different clinicopathological features, prognoses and sensitivity to treatment
Emerging data suggest that tumors not bearing BRCA1/2 mutations but exhibiting BRCA-related gene defects and DNA repair dysfunctions are potentially responsive to PARPibased therapy [4]
MiRNA expression profile was performed on a training set of 43 familial (22 BRCA1/2-related and 21 BRCAX) and 28 sporadic BC by microarray analyses

Summary

Introduction

Breast cancer (BC) is a complex disease characterized by high level of heterogeneity, different clinicopathological features, prognoses and sensitivity to treatment. BRCA1 and BRCA2 proteins play a pivotal role in leading high-fidelity repair of double-strand DNA breaks. Emerging data suggest that tumors not bearing BRCA1/2 mutations but exhibiting BRCA-related gene defects and DNA repair dysfunctions are potentially responsive to PARPibased therapy [4]. The term ‘BRCAness’ has been introduced to identify sporadic tumors sharing clinicopathological and molecular characteristics similar to those associated to BRCA1/2 germline mutations [5]. Among all mechanisms attributable to BRCA1 expression silencing, a major role has been assigned to microRNAs (miRNAs) [8]. MiRNAs are a class of small noncoding RNA of 20-27 nucleotides that act as negative regulators of gene expression at post transcriptional level [9]. We showed that BRCA-related and sporadic TNBCs shared a same miRNA cluster, suggesting a similar epigenetic regulation in these tumor subgroups

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