MiR-29b-1-5p is altered in BRCA1 mutant tumours and is a biomarker in basal-like breast cancer

// Michael J.G. Milevskiy 1, 2, * , Gurveen K. Sandhu 1, * , Anna Wronski 1, 3 , Darren Korbie 4 , Brooke L. Brewster 1 , Annette Shewan 1 , Stacey L. Edwards 1, 5 , Juliet D. French 1, 5 and Melissa A. Brown 1 1 School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, Queensland, Australia 2 Present Address: ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia 3 Present Address: Department of Developmental, Molecular and Chemical Biology, School of Medicine and Molecular Oncology Research Institute, Tufts University, Boston, Massachusetts, USA 4 Australian Institute of Biotechnology and Nanotechnology, University of Queensland, St Lucia, Queensland, Australia 5 QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia * Shared first Correspondence to: Michael J.G. Milevskiy, email: Milevskiy.m@wehi.edu.au Keywords: breast cancer; miRNA; biomarker; BRCA1 Received: May 13, 2018      Accepted: August 27, 2018      Published: September 11, 2018 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.