PRECLINICAL STUDY Integration of BRCA1-mediated miRNA and mRNA profiles reveals microRNA regulation of TRAF2 and NFjB pathway Miljana Tanic • Magdalena Zajac • Gonzalo Go ´mez-Lo ´pez • Javier Benı ´tez • Beatriz Martı ´nez-Delgado Received: 23 August 2011 / Accepted: 29 November 2011 Ó Springer Science+Business Media, LLC. 2011 Abstract Microarray-based techniques are being useful to obtain miRNA and gene expression signatures associated with different tumors. BRCA1 deregulation is a frequent event in the pathogenesis of breast as well as other cancers. In addition to DNA repair functions of BRCA1, it is involved in a wide range of cellular processes such as cell cycle, chromatin remodeling or transcription. However, the molecular events underlying BRCA1-associated tumorigenesis are still largely unknown. In order to deepen our understanding of BRCA1- associated tumorigenesis, we integrated data from mRNA and miRNA microarray experiments on HCC1937 breast cancer cell line, and the isogenic HCC1937 stably expressing BRCA1, to obtain significant miRNA–mRNA relationships associated with the presence of BRCA1 gene. By using bio- informatic integration of gene and miRNA expression data, we found significant miRNA–gene relationships underlying the array signatures. We additionally evaluated the role of these statistically significant pairs at the biological pathways level and identified MAPK and NF-jB pathways associated with these expression changes. Furthermore, we experimen- tally validated miRNAs induced by BRCA1 that commonly regulate TRAF2, a key regulator of NF-jB and MAPK path- ways. We demonstrate that miR-146a, miR-99b and miR-205, induced in HCC1937 BRCA1-expressing cells, bind and regulate TRAF2 gene. In addition, re-expression of miR-146a, miR-99b or miR-205 in HCC1937 BRCA1-null cells was sufficient to modulate NF-jB activity. Our results demon- strate that integration of mRNA and miRNA associated with BRCA1 expression was useful to discover new miRNA–gene interactions as molecular events underlying BRCA1-mediated tumorigenesis. Keywords BRCA1  Hereditary breast cancer  microRNA  mRNA expression  Data integration  TRAF2  NF-KappaB Introduction Loss of BRCA1 activity is a well-known factor for sus- ceptibility to breast and ovarian cancers [1–6]. Several BRCA1 functions have been demonstrated so far [7, 8], including DNA damage repair/recombination, cell cycle control [9], chromatin remodeling and ubiquitylation [10], and regulation of both transcriptional activation and repression [11, 12]. MicroRNAs (miRNAs) are a class of short non-coding RNA that act predominantly as negative regulators of gene expression at post-transcriptional level, by binding to the 3 0 UTR of their target genes. miRNAs play critical roles in control of various biological processes and are extensively implicated in cancer pathogenesis [13–17]. Individual miRNAs can have multiple targets, and each mRNA may be regulated by multiple miRNAs. Still, due to the scarcity Electronic supplementary material The online version of this article (doi:10.1007/s10549-011-1905-4) contains supplementary material, which is available to authorized users. M. Tanic  M. Zajac  J. Benı ´tez  B. Martı ´nez-Delgado (&) Human Genetics Group, Spanish National Cancer Research Centre (CNIO), Melchor Fernandez Almagro 3, Madrid 28029, Spain e-mail: bmartinez@cnio.es G. Go ´mez-Lo ´pez Bioinformatics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain J. Benı ´tez  B. Martı ´nez-Delgado Centro de Investigacio ´n Biome ´dica en Red de Enfermedades Raras (CIBERER), (CNIO), Madrid, Spain 123 Breast Cancer Res Treat DOI 10.1007/s10549-011-1905-4