Abstract
BackgroundUnderstanding 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.ResultsA 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.ConclusionThe 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.
Highlights
Understanding the molecular control of cell lineages and fate determination in complex tissues is key to understanding the developmental biology and cellular homeostasis of such tissues and for our understanding and interpretation of the molecular pathology of diseases such as cancer
To demonstrate that these populations corresponded to basal/myoepithelial, luminal estrogen receptor alpha (ER)- and luminal ER+ cells respectively, as we have previously described [5], relative gene expression levels of the basal cell marker Keratin 14 (Krt14), the luminal cell marker Keratin 18 (Krt18) and Estrogen Receptor α (Esr1) were measured by quantitative real-time rtPCR
This agreed with previous data [5] and with staining of sections through the mouse mammary gland (Figure 1A and 1B) which showed that the basal cells were Keratin 14+ (K14+), the luminal cells were keratin 18 (K18)+ and that ER+ cells were found exclusively in the K18+ luminal cell layer
Summary
Understanding the molecular control of cell lineages and fate determination in complex tissues is key to understanding the developmental biology and cellular homeostasis of such tissues and 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. The function of complex tissues, such as the mammary epithelium, is a product of the interactions between their constituent cell types In such tissues, disease states like cancer are essentially a failure of this cellular homeostasis and are characterised by insensitivity of cells to external regulatory factors and aberrant cell fate choices. A detailed molecular characterisation of the cell types in a complex tissue is essential for the interpretation of the molecular pathology of its diseases
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call