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.
journal_name
EMBO Mol Medjournal_title
EMBO molecular medicineauthors
Garcia AI,Buisson M,Bertrand P,Rimokh R,Rouleau E,Lopez BS,Lidereau R,Mikaélian I,Mazoyer Sdoi
10.1002/emmm.201100136subject
Has Abstractpub_date
2011-05-01 00:00:00pages
279-90issue
5eissn
1757-4676issn
1757-4684journal_volume
3pub_type
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