Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/103721
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Type: Journal article
Title: Integration of microRNA signatures of distinct mammary epithelial cell types with their gene expression and epigenetic portraits
Author: Pal, B.
Chen, Y.
Bert, A.
Hu, Y.
Sheridan, J.
Beck, T.
Shi, W.
Satterley, K.
Jamieson, P.
Goodall, G.
Lindeman, G.
Smyth, G.
Visvader, J.
Citation: Breast Cancer Research, 2015; 17(1):85-1-85-16
Publisher: Biomed Central
Issue Date: 2015
ISSN: 1465-542X
1465-5411
Statement of
Responsibility: 
Bhupinder Pal, Yunshun Chen, Andrew Bert, Yifang Hu, Julie M. Sheridan, Tamara Beck, Wei Shi, Keith Satterley, Paul Jamieson, Gregory J. Goodall, Geoffrey J. Lindeman, Gordon K. Smyth, and Jane E. Visvader
Abstract: Introduction: 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.
Keywords: MicroRNAs; gene expression profiling; gene expression regulation
Rights: © 2015 Pal et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated
DOI: 10.1186/s13058-015-0585-0
Grant ID: http://purl.org/au-research/grants/nhmrc/461221
http://purl.org/au-research/grants/nhmrc/490037
http://purl.org/au-research/grants/nhmrc/1008440
http://purl.org/au-research/grants/nhmrc/1016701
http://purl.org/au-research/grants/nhmrc/1054618
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