Abstract
Depletion of BRCA1 protein in mouse mammary glands results in defects in lactational development and increased susceptibility to mammary cancer. Extensive work has focussed on the role of BRCA1 in the normal breast and in the development of breast cancer, the cell of origin for BRCA1 tumours and the protein-coding genes altered in BRCA1 deficient cells. However, the role of non-coding RNAs in BRCA1-deficient cells is poorly understood. To evaluate miRNA expression in BRCA1 deficient mammary cells, RNA sequencing was performed on the mammary glands of Brca1 knockout mice. We identified 140 differentially expressed miRNAs, 9 of which were also differentially expressed in human BRCA1 breast tumours or familial non-BRCA1 patients and during normal gland development. We show that BRCA1 binds to putative cis-elements in promoter regions of the miRNAs with the potential to regulate their expression, and that four miRNAs (miR-29b-1-5p, miR-664, miR-16-2 and miR-744) significantly stratified the overall survival of basal-like tumours. Importantly the prognostic value of miR-29b-1-5p was higher in significance than several commonly used clinical biomarkers. These results emphasise the role of Brca1 in modulating expression of miRNAs and highlights the potential for BRCA1 regulated miRNAs to be informative biomarkers associated with BRCA1 loss and survival in breast cancer.
Highlights
Germline mutations in the breast cancer susceptibility gene, Breast Cancer 1 (BRCA1), confer a high risk of developing neoplastic lesions
Seq analysis was performed using RNA extracted from mammary glands at day 1 of lactation. 140 miRNAs were differentially expressed, of which 39 were down-regulated and 101 were up-regulated in MMTV-Cre/Brca1fl/fl glands compared to Brca1fl/fl controls (Figure 1A, Supplementary Table 1)
We examined the expression of miRNAs differentially expressed in Brca1 deficient murine mammary glands with those miRNAs altered in 13 breast tumours of human BRCA1 mutation carriers (Published cohort [17])
Summary
Germline mutations in the breast cancer susceptibility gene, BRCA1, confer a high risk of developing neoplastic lesions. BRCA1deficient breast tumours often present as difficult to treat triple negative breast cancers (TNBC) not dissimilar to the basal-like molecular subtype of breast cancer, which lack expression of hormone receptors and easy to target growth signals. Whilst significant discoveries have been www.oncotarget.com made on the contribution of the coding genome, the role of non-coding RNAs, such as microRNAs (miRNAs), in BRCA1-associated tumourigenesis remains unclear. MiRNAs are small non-coding RNA molecules that predominantly inhibit gene expression, posttranscriptionally [6]. MiRNAs have key roles in tumourigenesis and development of breast cancer with widespread affects across all hallmarks of cancer [7, 8]
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