Down-regulation of BRCA1 expression by miR-146a and miR-146b-5p in triple negative sporadic breast cancers.
Bottom Line: 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.
Affiliation: CNRS UMR5286 Inserm U1052, "Equipe Labellisée LIGUE 2008", University Lyon, Cancer Research Center of Lyon, Centre Léon Bérard, France.Show MeSH
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Mentions: BRCA1 has been repeatedly shown to inhibit cellular proliferation when overexpressed in different cell types (Abbott et al, 1999; Aprelikova et al, 1999; Holt et al, 1996). Conversely, BRCA1 depletion through RNA interference has been shown to stimulate proliferation. Therefore, we studied the consequences of miR-146a and miR-146b-5p expression in HeLa (Fig 4A) or MDA-MB-468 (Fig 4B) cells on proliferation. As expected, miR-146a and miR-146b-5p precursor transfection increased cell proliferation in HeLa and in MDA-MB-468 cells, as did BRCA1 siRNA (Fig S2 of Supporting Information). In HeLa cells, the increase of proliferation seen with miRNAs was equivalent to that obtained with siRNAs. Furthermore, in these latter cells, cotransfection with a BRCA1-expressing vector lacking the BRCA1 3′UTR [pBRCA1 (1–24)] and thus insensitive to miR-146a/b-5p did not produce any change in cell proliferation, indicating that the increase seen previously was linked to down-expression of BRCA1 (Fig 4A).
Affiliation: CNRS UMR5286 Inserm U1052, "Equipe Labellisée LIGUE 2008", University Lyon, Cancer Research Center of Lyon, Centre Léon Bérard, France.