MicroRNA deregulation in triple negative breast cancer reveals a role of miR-498 in regulating BRCA1 expression

// Nerea Matamala 1, 10 , Maria Teresa Vargas 2, 11 , Ricardo Gonzalez-Campora 2 , Jose Ignacio Arias 3 , Primitiva Menendez 4 , Eduardo Andres-Leon 5, 12 , Kira Yanowsky 1 , Ana Llaneza-Folgueras 6 , Rebeca Minambres 7 , Beatriz Martinez-Delgado 8 , Javier Benitez 1, 9 1 Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain 2 Pathology Service, Hospital Virgen de la Macarena, Sevilla, Spain 3 Surgery Service, Hospital Monte Naranco, Oviedo, Spain 4 Pathology Service, Hospital Monte Naranco, Oviedo, Spain 5 Bioinformatics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain 6 General Surgery Service, Hospital Universitario Central de Asturias, Oviedo, Espana 7 Projects Unit, Sistemas Genomicos, Valencia, Spain 8 Molecular Genetics Unit, Research Institute of Rare Diseases (IIER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain 9 Network on Rare Diseases (CIBERER), Madrid, Spain 10 Current address: Molecular Genetics Unit, Research Institute of Rare Diseases (IIER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain 11 Current address: Hematology Service, Hospital Virgen de la Macarena, Sevilla, Spain 12 Current address: Bioinformatics Unit, Instituto de Parasitologia y Biomedicina “Lopez Neyra”, Consejo Superior de Investigaciones Cientificas (IPBLN-CSIC), Granada, Spain Correspondence to: Javier Benitez, e-mail: jbenitez@cnio.es Keywords: BRCA1, microRNA, triple negative breast cancer Received: November 09, 2015     Accepted: February 16, 2016     Published: February 25, 2016 ABSTRACT Emerging evidence suggests that BRCA1 pathway contributes to the behavior of sporadic triple negative breast cancer (TNBC), but little is known about the mechanisms underlying this association. Considering the central role that microRNAs (miRNAs) play in gene expression regulation, the aim of this study was to identify miRNAs specifically deregulated in TNBC and investigate their involvement in BRCA1 regulation. Using locked nucleic acid (LNA)-based microarrays, expression levels of 1919 miRNAs were measured in paraffin-embedded tissues from 122 breast tumors and 11 healthy breast tissue samples. Differential miRNA expression was explored among the main subtypes of breast cancer, and 105 miRNAs were identified as specific for triple negative tumors. In silico prediction revealed that miR-498 and miR-187-5p target BRCA1 , and these results were confirmed by luciferase reporter assay. While miR-187-5p was found overexpressed in a luminal B cell line, miR-498 was highly expressed in a triple negative cell line, Hs578T, and its expression was negatively correlated with the levels of BRCA1 . We functionally demonstrated that miR-498 inhibits BRCA1 in breast cancer cell lines, and showed that inhibition of miR-498 led to reduced proliferation in the triple negative cell line Hs578T. Our results indicate that miR-498 regulates BRCA1 expression in breast cancer and its overexpression could contribute to the pathogenesis of sporadic TNBC via BRCA1 downregulation.