title: Integration of microRNA signatures of distinct mammary epithelial cell types with their gene expression and epigenetic portraits.
abstract: BACKGROUND
  MicroRNAs (miRNAs) have been implicated in governing lineage specification and differentiation in multiple organs; however, little is known about their specific roles in mammopoiesis. We have determined the global miRNA expression profiles of functionally distinct epithelial subpopulations in mouse and human mammary tissue, and compared these to their cognate transcriptomes and epigenomes. Finally, the human miRNA signatures were used to interrogate the different subtypes of breast cancer, with a view to determining miRNA networks deregulated during oncogenesis.
  
  
  METHODS
  RNA from sorted mouse and human mammary cell subpopulations was subjected to miRNA expression analysis using the TaqMan MicroRNA Array. Differentially expressed (DE) miRNAs were correlated with gene expression and histone methylation profiles. Analysis of miRNA signatures of the intrinsic subtypes of breast cancer in The Cancer Genome Atlas (TCGA) database versus those of normal human epithelial subpopulations was performed.
  
  
  RESULTS
  Unique miRNA signatures characterized each subset (mammary stem cell (MaSC)/basal, luminal progenitor, mature luminal, stromal), with a high degree of conservation across species. Comparison of miRNA and transcriptome profiles for the epithelial subtypes revealed an inverse relationship and pinpointed key developmental genes. Interestingly, expression of the primate-specific miRNA cluster (19q13.4) was found to be restricted to the MaSC/basal subset. Comparative analysis of miRNA signatures with H3 lysine modification maps of the different epithelial subsets revealed a tight correlation between active or repressive marks for the top DE miRNAs, including derepression of miRNAs in Ezh2-deficient cellular subsets. Interrogation of TCGA-identified miRNA profiles with the miRNA signatures of different human subsets revealed specific relationships.
  
  
  CONCLUSIONS
  The derivation of global miRNA expression profiles for the different mammary subpopulations provides a comprehensive resource for understanding the interplay between miRNA networks and target gene expression. These data have highlighted lineage-specific miRNAs and potential miRNA-mRNA networks, some of which are disrupted in neoplasia. Furthermore, our findings suggest that key developmental miRNAs are regulated by global changes in histone modification, thus linking the mammary epigenome with genome-wide changes in the expression of genes and miRNAs. Comparative miRNA signature analyses between normal breast epithelial cells and breast tumors confirmed an important linkage between luminal progenitor cells and basal-like tumors.
authors.affiliation: ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia. pal@wehi.edu.au.|Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3010, Australia. pal@wehi.edu.au.
authors.forename: Bhupinder
authors.initials: B
authors.lastname: Pal
authors.affiliation: Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3010, Australia. yuchen@wehi.edu.au.|Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia. yuchen@wehi.edu.au.
authors.forename: Yunshun
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, 5000, Australia. andrew.bert@health.sa.gov.au.
authors.forename: Andrew
authors.initials: A
authors.lastname: Bert
authors.affiliation: Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia. hu@wehi.edu.au.
authors.forename: Yifang
authors.initials: Y
authors.lastname: Hu
authors.affiliation: ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia. sheridan@wehi.edu.au.|Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3010, Australia. sheridan@wehi.edu.au.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Sheridan
authors.affiliation: ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia. mclennan@wehi.edu.au.|Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3010, Australia. mclennan@wehi.edu.au.
authors.forename: Tamara
authors.initials: T
authors.lastname: Beck
authors.affiliation: Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia. shi@wehi.edu.au.|Department of Computing and Information Systems, The University of Melbourne, Parkville, VIC, 3010, Australia. shi@wehi.edu.au.
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.affiliation: Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia. keith@wehi.edu.au.
authors.forename: Keith
authors.initials: K
authors.lastname: Satterley
authors.affiliation: ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia. jamieson.p@wehi.eu.au.|Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3010, Australia. jamieson.p@wehi.eu.au.
authors.forename: Paul
authors.initials: P
authors.lastname: Jamieson
authors.affiliation: Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, 5000, Australia. Greg.Goodall@health.sa.gov.au.|School of Medicine and School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA, 5005, Australia. Greg.Goodall@health.sa.gov.au.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Goodall
authors.affiliation: ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia. lindeman@wehi.edu.au.|Department of Medicine, The University of Melbourne, Parkville, VIC, 3010, Australia. lindeman@wehi.edu.au.|Department of Medical Oncology, The Royal Melbourne Hospital, Parkville, VIC, 3010, Australia. lindeman@wehi.edu.au.
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Lindeman
authors.affiliation: Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia. smyth@wehi.edu.au.|Department of Mathematics and Statistics, The University of Melbourne, Parkville, VIC, 3010, Australia. smyth@wehi.edu.au.
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Smyth
authors.affiliation: ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia. visvader@wehi.edu.au.|Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3010, Australia. visvader@wehi.edu.au.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Visvader
mesh_terms: D000818:Animals; D001940:Breast / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D019070:Cell Lineage / Q000235:genetics; D016000:Cluster Analysis; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D056426:Genetic Loci; D006801:Humans; D008321:Mammary Glands, Animal / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D059467:Transcriptome
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger