Subtype-specific micro-RNA expression signatures in breast cancer progression

Abstract

Robust markers of invasiveness may help reduce the overtreatment of in situ carcinomas. Breast cancer is a heterogeneous disease and biological mechanisms for carcinogenesis vary between subtypes. Stratification by subtype is therefore necessary in order to identify relevant and robust signatures of invasive disease. We have identified miRNA alterations during breast cancer progression in two separate datasets and used stratification and external validation to strengthen the findings.

We analysed two separate datasets (METABRIC and AHUS) consisting of a total of 186 normal breast tissue samples, 18 ductal carcinoma in situ (DCIS) and 1338 invasive breast carcinomas. Validation in a separate dataset and stratification by molecular subtypes based on immunohistochemistry, PAM50 and integrated cluster classifications were performed.

We propose subtype-specific miRNA signatures of invasive carcinoma and a validated signature of DCIS. miRNAs included in the invasive signatures include down-regulation of miR-139-5p in aggressive subtypes and up-regulation of miR-29c-5p expression in the luminal subtypes. No miRNAs were differentially expressed in the transition from DCIS to invasive carcinomas on the whole, indicating the need for subtype stratification. A total of 27 miRNAs were included in our proposed DCIS-signature. Significant alterations of expression included up-regulation of miR-21-5p and the miR-200-family and down-regulation of let-7 family members in DCIS samples. The signatures proposed here can form the basis for studies exploring DCIS samples with increased invasive potential and serum biomarkers for in situ and invasive breast cancer. This article is protected by copyright. All rights reserved.

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