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Integration of BRCA1-mediated miRNA and mRNA profiles reveals microRNA regulation of TRAF2 and NFκB pathway

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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 bioinformatic 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-κB pathways associated with these expression changes. Furthermore, we experimentally validated miRNAs induced by BRCA1 that commonly regulate TRAF2, a key regulator of NF-κB and MAPK pathways. 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-κB activity. Our results demonstrate 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.

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Acknowledgments

We thank Alicia Barroso, Fernando Fernandez and Victoria Fernandez for excellent technical assistance. This study was supported by grants from the Asociación Española contra el cancer (AECC). MT has financial support by Fundacion La Caixa. The CIBER de Enfermedades Raras is an initiative of the ISCIII.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Human Genetics Group, Spanish National Cancer Research Centre (CNIO), Melchor Fernandez Almagro 3, Madrid, 28029, Spain

    Miljana Tanic, Magdalena Zajac, Javier Benítez & Beatriz Martínez-Delgado

  2. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), (CNIO), Madrid, Spain

    Javier Benítez & Beatriz Martínez-Delgado

  3. Bioinformatics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    Gonzalo Gómez-López

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  1. Miljana Tanic
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  2. Magdalena Zajac
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  4. Javier Benítez
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  5. Beatriz Martínez-Delgado
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Correspondence to Beatriz Martínez-Delgado.

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Tanic, M., Zajac, M., Gómez-López, G. et al. Integration of BRCA1-mediated miRNA and mRNA profiles reveals microRNA regulation of TRAF2 and NFκB pathway. Breast Cancer Res Treat 134, 41–51 (2012). https://doi.org/10.1007/s10549-011-1905-4

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