Abstract 1817P
Background
Germline mutations in the BRCA1 gene confer an increased lifetime risk of developing ovarian and breast cancer (BC). BRCA1-associated BCs are often triple negative (TNBC), an aggressive type of BC characterized by lack of estrogen, progesterone, and HER2 receptor expression. BRCA1 is involved in several biological processes, including DNA double-break repair, RNA transcription, splicing control, and microRNA (miRNA) maturation. However, how BRCA1 inactivation may promote the gain of specific BC phenotypes remains to be elucidated. In an attempt to shed light on this issue, we examined two large BC cohorts for expression of coding and non-coding RNAs and DNA methylation status.
Methods
miRNA and DNA methylation data were retrieved from two large BC cohorts, TCGA (n = 814) and Metabric (n = 1283) datasets. Chen and coworkers' classification of BRCA1-like and non-BRCA1-like tumors was used as an estimate of BRCA1 deregulation. Gene expression analyses, methylation correlations, and functional annotations were performed.
Results
We identified a core of miRNAs downregulated in BRCA1-like tumors versus non-BRCA1-like tumors from both cohorts. Among these, we focused on miR-29 family members found to be inversely correlated with the expression of their cognate targets in BRCA1-like tumors. For two miR-29 targets, the methyltransferases DNMT3A and DNMT3B, a correlation was observed with the methylation status of CpGs controlling the expression of estrogen receptor alpha (ESR1).
Conclusions
Integration of multi-omics data allowed us to discover a novel miR-29/DNMT3A-3B/ESR1 axis possibly controlled by BRCA1. This network may contribute to the receptor-negative phenotype of BRCA1-mutated tumors. It also highlights the potential of BRCA1-regulated miRNAs as biomarkers for BRCA1 deficiency.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
This study was supported by the Italian Ministry of Health.
Disclosure
All authors have declared no conflicts of interest.