title: Transcriptome analysis of mammary epithelial subpopulations identifies novel determinants of lineage commitment and cell fate.
abstract: BACKGROUND
  Understanding the molecular control of cell lineages and fate determination in complex tissues is key to not only understanding the developmental biology and cellular homeostasis of such tissues but also for our understanding and interpretation of the molecular pathology of diseases such as cancer. The prerequisite for such an understanding is detailed knowledge of the cell types that make up such tissues, including their comprehensive molecular characterisation. In the mammary epithelium, the bulk of the tissue is composed of three cell lineages, namely the basal/myoepithelial, luminal epithelial estrogen receptor positive and luminal epithelial estrogen receptor negative cells. However, a detailed molecular characterisation of the transcriptomic differences between these three populations has not been carried out.
  
  
  RESULTS
  A whole transcriptome analysis of basal/myoepithelial cells, luminal estrogen receptor negative cells and luminal estrogen receptor positive cells isolated from the virgin mouse mammary epithelium identified 861, 326 and 488 genes as highly differentially expressed in the three cell types, respectively. Network analysis of the transcriptomic data identified a subpopulation of luminal estrogen receptor negative cells with a novel potential role as non-professional immune cells. Analysis of the data for potential paracrine interacting factors showed that the basal/myoepithelial cells, remarkably, expressed over twice as many ligands and cell surface receptors as the other two populations combined. A number of transcriptional regulators were also identified that were differentially expressed between the cell lineages. One of these, Sox6, was specifically expressed in luminal estrogen receptor negative cells and functional assays confirmed that it maintained mammary epithelial cells in a differentiated luminal cell lineage.
  
  
  CONCLUSIONS
  The mouse mammary epithelium is composed of three main cell types with distinct gene expression patterns. These suggest the existence of a novel functional cell type within the gland, that the basal/myoepithelial cells are key regulators of paracrine signalling and that there is a complex network of differentially expressed transcription factors controlling mammary epithelial cell fate. These data will form the basis for understanding not only cell fate determination and cellular homeostasis in the normal mammary epithelium but also the contribution of different mammary epithelial cell types to the etiology and molecular pathology of breast disease.
authors.affiliation: Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK. howard.kendrick@icr.ac.uk
authors.forename: Howard
authors.initials: H
authors.lastname: Kendrick
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Regan
authors.forename: Fiona-Ann
authors.initials: FA
authors.lastname: Magnay
authors.forename: Anita
authors.initials: A
authors.lastname: Grigoriadis
authors.forename: Costas
authors.initials: C
authors.lastname: Mitsopoulos
authors.forename: Marketa
authors.initials: M
authors.lastname: Zvelebil
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Smalley
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D016000:Cluster Analysis; D019295:Computational Biology; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D020869:Gene Expression Profiling; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D055755:SOXD Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D011960:Receptors, Estrogen; D055755:SOXD Transcription Factors; C095939:Sox6 protein, mouse