Transcriptome analyses of mouse and human mammary cell subpopulations reveal multiple conserved genes and pathways

Elgene Lim, Di Wu, Bhupinder Pal, Toula Bouras, Marie-Liesse Labat, François Vaillant, Hideo Yagita, Geoffrey J. Lindeman, Gordon K. Smyth, Jane E. Visvader

Research output: Contribution to journalArticle

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Abstract

Introduction: Molecular characterization of the normal epithelial cell types that reside in the mammary gland is an important step toward understanding pathways that regulate self-renewal, lineage commitment, and differentiation along the hierarchy. Here we determined the gene expression signatures of four distinct subpopulations isolated from the mouse mammary gland. The epithelial cell signatures were used to interrogate mouse models of mammary tumorigenesis and to compare with their normal human counterpart subsets to identify conserved genes and networks.Methods: RNA was prepared from freshly sorted mouse mammary cell subpopulations (mammary stem cell (MaSC)-enriched, committed luminal progenitor, mature luminal and stromal cell) and used for gene expression profiling analysis on the Illumina platform. Gene signatures were derived and compared with those previously reported for the analogous normal human mammary cell subpopulations. The mouse and human epithelial subset signatures were then subjected to Ingenuity Pathway Analysis (IPA) to identify conserved pathways.Results: The four mouse mammary cell subpopulations exhibited distinct gene signatures. Comparison of these signatures with the molecular profiles of different mouse models of mammary tumorigenesis revealed that tumors arising in MMTV-Wnt-1 and p53-/- mice were enriched for MaSC-subset genes, whereas the gene profiles of MMTV-Neu and MMTV-PyMT tumors were most concordant with the luminal progenitor cell signature. Comparison of the mouse mammary epithelial cell signatures with their human counterparts revealed substantial conservation of genes, whereas IPA highlighted a number of conserved pathways in the three epithelial subsets.Conclusions: The conservation of genes and pathways across species further validates the use of the mouse as a model to study mammary gland development and highlights pathways that are likely to govern cell-fate decisions and differentiation. It is noteworthy that many of the conserved genes in the MaSC population have been considered as epithelial-mesenchymal transition (EMT) signature genes. Therefore, the expression of these genes in tumor cells may reflect basal epithelial cell characteristics and not necessarily cells that have undergone an EMT. Comparative analyses of normal mouse epithelial subsets with murine tumor models have implicated distinct cell types in contributing to tumorigenesis in the different models.

Original languageEnglish (US)
Article numberR21
JournalBreast Cancer Research
Volume12
Issue number2
DOIs
StatePublished - Mar 26 2010
Externally publishedYes

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Gene Expression Profiling
Breast
Genes
Stem Cells
Human Mammary Glands
Epithelial Cells
Carcinogenesis
Epithelial-Mesenchymal Transition
Neoplasms
Gene Regulatory Networks
Stromal Cells
Transcriptome
RNA
Gene Expression

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Transcriptome analyses of mouse and human mammary cell subpopulations reveal multiple conserved genes and pathways. / Lim, Elgene; Wu, Di; Pal, Bhupinder; Bouras, Toula; Labat, Marie-Liesse; Vaillant, François; Yagita, Hideo; Lindeman, Geoffrey J.; Smyth, Gordon K.; Visvader, Jane E.

In: Breast Cancer Research, Vol. 12, No. 2, R21, 26.03.2010.

Research output: Contribution to journalArticle

Lim, E, Wu, D, Pal, B, Bouras, T, Labat, M-L, Vaillant, F, Yagita, H, Lindeman, GJ, Smyth, GK & Visvader, JE 2010, 'Transcriptome analyses of mouse and human mammary cell subpopulations reveal multiple conserved genes and pathways', Breast Cancer Research, vol. 12, no. 2, R21. https://doi.org/10.1186/bcr2560
Lim, Elgene ; Wu, Di ; Pal, Bhupinder ; Bouras, Toula ; Labat, Marie-Liesse ; Vaillant, François ; Yagita, Hideo ; Lindeman, Geoffrey J. ; Smyth, Gordon K. ; Visvader, Jane E. / Transcriptome analyses of mouse and human mammary cell subpopulations reveal multiple conserved genes and pathways. In: Breast Cancer Research. 2010 ; Vol. 12, No. 2.
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abstract = "Introduction: Molecular characterization of the normal epithelial cell types that reside in the mammary gland is an important step toward understanding pathways that regulate self-renewal, lineage commitment, and differentiation along the hierarchy. Here we determined the gene expression signatures of four distinct subpopulations isolated from the mouse mammary gland. The epithelial cell signatures were used to interrogate mouse models of mammary tumorigenesis and to compare with their normal human counterpart subsets to identify conserved genes and networks.Methods: RNA was prepared from freshly sorted mouse mammary cell subpopulations (mammary stem cell (MaSC)-enriched, committed luminal progenitor, mature luminal and stromal cell) and used for gene expression profiling analysis on the Illumina platform. Gene signatures were derived and compared with those previously reported for the analogous normal human mammary cell subpopulations. The mouse and human epithelial subset signatures were then subjected to Ingenuity Pathway Analysis (IPA) to identify conserved pathways.Results: The four mouse mammary cell subpopulations exhibited distinct gene signatures. Comparison of these signatures with the molecular profiles of different mouse models of mammary tumorigenesis revealed that tumors arising in MMTV-Wnt-1 and p53-/- mice were enriched for MaSC-subset genes, whereas the gene profiles of MMTV-Neu and MMTV-PyMT tumors were most concordant with the luminal progenitor cell signature. Comparison of the mouse mammary epithelial cell signatures with their human counterparts revealed substantial conservation of genes, whereas IPA highlighted a number of conserved pathways in the three epithelial subsets.Conclusions: The conservation of genes and pathways across species further validates the use of the mouse as a model to study mammary gland development and highlights pathways that are likely to govern cell-fate decisions and differentiation. It is noteworthy that many of the conserved genes in the MaSC population have been considered as epithelial-mesenchymal transition (EMT) signature genes. Therefore, the expression of these genes in tumor cells may reflect basal epithelial cell characteristics and not necessarily cells that have undergone an EMT. Comparative analyses of normal mouse epithelial subsets with murine tumor models have implicated distinct cell types in contributing to tumorigenesis in the different models.",
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AU - Wu, Di

AU - Pal, Bhupinder

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AU - Labat, Marie-Liesse

AU - Vaillant, François

AU - Yagita, Hideo

AU - Lindeman, Geoffrey J.

AU - Smyth, Gordon K.

AU - Visvader, Jane E.

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AB - Introduction: Molecular characterization of the normal epithelial cell types that reside in the mammary gland is an important step toward understanding pathways that regulate self-renewal, lineage commitment, and differentiation along the hierarchy. Here we determined the gene expression signatures of four distinct subpopulations isolated from the mouse mammary gland. The epithelial cell signatures were used to interrogate mouse models of mammary tumorigenesis and to compare with their normal human counterpart subsets to identify conserved genes and networks.Methods: RNA was prepared from freshly sorted mouse mammary cell subpopulations (mammary stem cell (MaSC)-enriched, committed luminal progenitor, mature luminal and stromal cell) and used for gene expression profiling analysis on the Illumina platform. Gene signatures were derived and compared with those previously reported for the analogous normal human mammary cell subpopulations. The mouse and human epithelial subset signatures were then subjected to Ingenuity Pathway Analysis (IPA) to identify conserved pathways.Results: The four mouse mammary cell subpopulations exhibited distinct gene signatures. Comparison of these signatures with the molecular profiles of different mouse models of mammary tumorigenesis revealed that tumors arising in MMTV-Wnt-1 and p53-/- mice were enriched for MaSC-subset genes, whereas the gene profiles of MMTV-Neu and MMTV-PyMT tumors were most concordant with the luminal progenitor cell signature. Comparison of the mouse mammary epithelial cell signatures with their human counterparts revealed substantial conservation of genes, whereas IPA highlighted a number of conserved pathways in the three epithelial subsets.Conclusions: The conservation of genes and pathways across species further validates the use of the mouse as a model to study mammary gland development and highlights pathways that are likely to govern cell-fate decisions and differentiation. It is noteworthy that many of the conserved genes in the MaSC population have been considered as epithelial-mesenchymal transition (EMT) signature genes. Therefore, the expression of these genes in tumor cells may reflect basal epithelial cell characteristics and not necessarily cells that have undergone an EMT. Comparative analyses of normal mouse epithelial subsets with murine tumor models have implicated distinct cell types in contributing to tumorigenesis in the different models.

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