title: Comparative microRNA profiling of sporadic and BRCA1 associated basal-like breast cancers.
abstract: BACKGROUND
  While a number of studies have examined miRNA profiles across the molecular subtypes of breast cancer, it is unclear whether BRCA1 basal-like cancers have a specific miRNA profile. This study aims to compare grade independent miRNA expression in luminal cancers, sporadic and BRCA1 basal-type breast cancers. It also aims to ascertain an immunohistochemical profile regulated by BRCA1 specific miRNAs for potential diagnostic use.
  
  
  METHODS
  miRNA expression was assessed in 11 BRCA1 basal, 16 sporadic basal, 17 luminal grade 3 cancers via microarrays. The expression of Cyclin D1, FOXP1, FIH-1, pan-ERβ, NRP1 and CD99, predicted to be regulated by BRCA1 specific miRNAs by computer prediction algorithms, was assessed via immunohistochemistry in a cohort of 35 BRCA1 and 52 sporadic basal-like cancers. Assessment of cyclin D1, FOXP1, NRP1 and CD99 expression was repeated on a validation cohort of 82 BRCA1 and 65 sporadic basal-like breast cancers.
  
  
  RESULTS
  Unsupervised clustering of basal cancers resulted in a "sporadic" cluster of 11 cancers, and a "BRCA1" cluster of 16 cancers, including a subgroup composed entirely of 10 BRCA1 cancers. Compared with sporadic basal cancers, BRCA1 cancers showed reduced positivity for proteins predicted to be regulated by miRNAs: FOXP1 (6/20[30 %] vs. 37/49[76 %], p < 0.001), cyclin D1 (8/22[36 %] vs. 30/46[65 %], p = 0.025), NRP1 (2/20[10 %] vs. 23/46[50 %], p = 0.002). This was confirmed in the validation cohort (all p < 0.001). Negative staining for 2 or more out of FOXP1, cyclin D1 and NRP1 predicts germline BRCA1 mutation with a sensitivity of 92 %, specificity of 44 %, positive predictive value of 38 % and a negative predictive value of 94 %.
  
  
  CONCLUSIONS
  Sporadic and BRCA1 basal-like cancers have grade independent miRNA expression profiles. Furthermore miRNA driven differences in the expression of proteins in BRCA1 basal cancers may be detected via immunohistochemistry. These findings may have important diagnostic implications, as immunohistochemical assessment of basal cancers, in addition to the patient's family and clinical history, may potentially identify patients who may benefit from BRCA1 gene testing.
authors.affiliation: Department of Anatomical Pathology, Prince of Wales Hospital, School of Medical Sciences, University of New South Wales, Randwick, 2031, Australia. max.yan@sesiahs.health.nsw.gov.au.
authors.forename: Max
authors.initials: M
authors.lastname: Yan
authors.affiliation: Baker IDI Heart and Diabetes Institute, Prahran, 3004, Australia. kristy.shield@bakeridi.edu.au.
authors.forename: Kristy
authors.initials: K
authors.lastname: Shield-Artin
authors.affiliation: Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, 3002, Australia. david.byrne@petermac.org.
authors.forename: David
authors.initials: D
authors.lastname: Byrne
authors.affiliation: Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, 3002, Australia. siddhartha.deb@petermac.org.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Deb
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, St Lucia, Australia. nick.waddell@imb.uq.edu.au.
authors.forename: Nic
authors.initials: N
authors.lastname: Waddell
authors.affiliation: Baker IDI Heart and Diabetes Institute, Prahran, 3004, Australia. izhak.haviv@bakeridi.edu.au.
authors.forename: Izhak
authors.initials: I
authors.lastname: Haviv
authors.affiliation: Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, 3002, Australia. stephen.fox@petermac.org.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Fox
mesh_terms: D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D019398:Genes, BRCA1; D056726:Genetic Association Studies; D006801:Humans; D007150:Immunohistochemistry; D035683:MicroRNAs / Q000235:genetics*; D009154:Mutation; D060787:Neoplasm Grading; D018295:Neoplasms, Basal Cell / Q000235:genetics* / Q000473:pathology; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D059467:Transcriptome
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs; D012333:RNA, Messenger