title: Down-regulation of BRCA1 expression by miR-146a and miR-146b-5p in triple negative sporadic breast cancers.
abstract: Germ-line mutations in the BRCA1 gene strongly predispose women to breast cancer (lifetime risk up to 80%). Furthermore, the BRCA1 protein is absent or present at very low levels in about one third of sporadic breast cancers. However, the mechanisms underlying BRCA1 somatic inactivation appear multiple and are still not fully understood. We report here the involvement of miR-146a and miR-146b-5p that bind to the same site in the 3'UTR of BRCA1 and down-regulate its expression as demonstrated using reporter assays. This was further confirmed with the endogenous BRCA1 gene by transfecting microRNA (miRNA) precursors or inhibitors in mammary cell lines. This down-regulation was accompanied by an increased proliferation and a reduced homologous recombination rate, two processes controlled by BRCA1. Furthermore, we showed that the highest levels of miR-146a and/or miR-146b-5p are found in basal-like mammary tumour epithelial cell lines and in triple negative breast tumours, which are the closest to tumours arising in carriers of BRCA1 mutations. This work provides further evidence for the involvement of miRNAs in sporadic breast cancer through down-regulation of BRCA1.
authors.affiliation: CNRS UMR5286 Inserm U1052, "Equipe Labellisée LIGUE 2008", University Lyon, Cancer Research Center of Lyon, Centre Léon Bérard, France.
authors.forename: Amandine I
authors.initials: AI
authors.lastname: Garcia
authors.forename: Monique
authors.initials: M
authors.lastname: Buisson
authors.forename: Pascale
authors.initials: P
authors.lastname: Bertrand
authors.forename: Ruth
authors.initials: R
authors.lastname: Rimokh
authors.forename: Etienne
authors.initials: E
authors.lastname: Rouleau
authors.forename: Bernard S
authors.initials: BS
authors.lastname: Lopez
authors.forename: Rosette
authors.initials: R
authors.lastname: Lidereau
authors.forename: Ivan
authors.initials: I
authors.lastname: Mikaélian
authors.forename: Sylvie
authors.initials: S
authors.lastname: Mazoyer
mesh_terms: D019313:BRCA1 Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D001943:Breast Neoplasms / Q000503:physiopathology*; D002277:Carcinoma / Q000503:physiopathology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D011995:Recombination, Genetic
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; C542542:MIRN146 microRNA, human; D035683:MicroRNAs