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Axes of differentiation in breast cancer: untangling stemness, lineage identity, and the epithelial to mesenchymal transition

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Differentiation‐associated regulatory programs are central in determining tumor phenotype, and contribute to heterogeneity between tumors and between individual cells within them. The transcriptional programs that control luminal and basal lineage identity in the normal mammary epithelium, as well as progenitor and stem cell function, are active in breast cancers, and show distinct associations with different disease subtypes. Also active in some tumors is the epithelial to mesenchymal transition (EMT) program, which endows carcinoma cells with mesenchymal as well as stem cell traits. The differentiation state of breast cancer cells is thus dictated by the complex combination of regulatory programs, and these can dramatically affect tumor growth and metastatic capacity. Breast cancer differentiation is often viewed along an axis between a basal–mesenchymal–stem cell state and a luminal–epithelial–differentiated state. Here we consider the links, as well as the distinctions, between the three components of this axis: basal versus luminal, mesenchymal versus epithelial, and stem cell versus differentiated identity. Analysis on a multidimensional scale, in which each of these axes is assessed separately, may offer increased resolution of tumor differentiation state. Cancer cells possessing a high degree of stemness would display increased capacity to shift between positions on such a multidimensional scale, and to acquire intermediate phenotypes on its different axes. Further molecular analysis of breast cancer cells with a focus on single‐cell profiling, and the development of improved tools for dissection of the circuits controlling gene activity, are essential for the elucidation of the programs dictating breast cancer differentiation state. WIREs Syst Biol Med 2014, 6:93–106. doi: 10.1002/wsbm.1252

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Axes of differentiation in the normal and cancerous breast. (a) Alignment of breast cancer subtypes (bottom) on a combined linear axis representing linked differentiation states: stem cell to differentiated, basal to luminal, and mesenchymal to epithelial. (b) The same differentiation axes, now positioned in a three dimensional scale, with spheres illustrating potential positions of breast cancer subtypes. The red sphere represents tumors containing cells with high plasticity, which are able to transition (arrows) between differentiation states (e.g., Claudin‐low tumors). The green sphere represents tumors with low plasticity, such as Luminal tumors.
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Cell lineages in the normal mammary epithelium. (a) Methodology of mammary epithelial lineage separation and profiling. Left: image of normal mammary epithelial ducts, the outer basal/myoepithelial layer is marked by CK14 (red) and the inner luminal layer is marked by CK18 (green). Right: schematic FACS plot representing the separation and isolation of the indicated cell populations by EpCAM and CD49f staining, followed by messenger RNA profiling. (b) A model for the differentiation hierarchy in the normal mammary epithelium. Cell types potentially located in the basal compartment, including bipotent mammary stem cells (MaSCs), are colored red, luminal progenitors are colored orange, and mature luminal cells are colored green. The uncertainty of the contribution of basal MaSCs to the luminal lineage in the adult is marked by a dashed arrow. Potential subtypes of luminal progenitors, e.g., ER+ and ER−, are indicated. Some of the regulatory transcription factors included in the lineage‐specific signatures are noted adjacent to each cell type, with dark font indicating genes for which experimental evidence for function in the gland exists. (c) Two possible scenarios representing the stem cell capacity of basal cells: left—a small subpopulation of MaSCs in the basal compartment possesses high gland reconstitution capacity; right—all basal cells possess limited reconstitution capacity.
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The epithelial to mesenchymal transition (EMT) signature in the normal and cancerous breast. (a) Correlation scores of the core EMT signature in breast cancers of different subtypes (left), as in Figure (a). A similar analysis was originally published in Taube et al. The signature includes genes consistently up or downregulated (twofold or more) in human mammary epithelial cells induced to undergo EMT by different factors. Graph on right shows same analysis on cancer stem cells (CSCs; CD44high/CD24low) versus non‐CSCs (CD44low/CD24high), isolated from breast cancer patients and expression profiled. (b) Average expression levels in the same breast cancer groups of individual known EMT transcriptional regulators. SNAI2=SLUG, SNAI1=SNAIL. (c) Correlation scores of the Core EMT signature in normal breast lineages, expression data from Lim et al. (d) Average expression levels of EMT transcriptional regulators in normal lineages, as well as of the mesenchymal marker Vimentin (VIM). (e) Scheme of two possible relationships between EMT and stemness. The purple line indicates a linear correlation with mesenchymal cells showing the highest level of stemness; the blue line shows the highest degree of stemness at an intermediate position on the M↔E axis, with low plasticity of fully mesenchymal or epithelial cells.
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Breast cancer subtypes and normal mammary lineage signatures. (a) Correlation scores of each of the normal lineage signatures in breast cancers of different subtypes. Similar analyses were originally published in Lim et al. Expression profiles of 918 tumors were obtained from The Cancer Genome Atlas and classified using the PAM50 classifier (https://genome.unc.edu/pubsup/breastGEO/Guide%20to%20Intrinsic%20Subtyping%209‐6‐10.pdf). A correlation score was calculated for each signature in each tumor, as described in Creighton et al. and box plots represent distribution of the scores of tumors in each subtype. Higher scores indicate a better correlation between the expression levels of signature genes in the tumors and in the normal lineage. (b) Average expression levels in the same breast cancer groups of individual transcription regulators included in each of the lineage signatures. Values are presented in Log2 and normalized to the mean expression across all samples (=0).
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Relationships between stemness and basal–luminal lineage identity. (a) A differentiation axis showing flow from mammary stem cells (possessing basal identity), to luminal progenitors, to mature luminal cells. (b) Illustration on a two‐axis scale of potential relationships between stemness, represented on the S↔D axis, and basal versus luminal lineage identity, represented on the B↔L axis. Left: a linear relationship, identical to (a); center: mammary stem cells (MaSCs) are distinct from differentiated basal/myoepithelial cells and possess an intermediate basal–luminal phenotype; right: the luminal and basal lineages are each maintained by distinct progenitors. B/Myo, basal/myoepithelial; LP, luminal progenitor; BP, basal progenitor.
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Merryn Tawhai

Merryn Tawhai

Dr. Tawhai is PI for lung modeling activities at the Auckland Bioengineering Institute and adjunct Associate Professor of Biomedical Engineering at the University of Iowa. Her research centers on developing multi-scale and multi-physics computational models of structure and function in the lung. A theme that runs through all of her work is the relationship between regional changes in lung structure or function and standard integrated measurements of the lung that are made at the mouth.

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