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Review
. 2015:112:353-82.
doi: 10.1016/bs.ctdb.2014.12.001. Epub 2015 Feb 11.

Adhesion in mammary development: novel roles for E-cadherin in individual and collective cell migration

Eliah R Shamir  1 , Andrew J Ewald  2
Affiliations
Review

Adhesion in mammary development: novel roles for E-cadherin in individual and collective cell migration

Eliah R Shamir et al. Curr Top Dev Biol. 2015.

Abstract

Epithelial tissues are essential for barrier function, secretion, and regulation of fluid transport. Their function requires cell polarity and cell-cell adhesion, mediated through intercellular junctions. Conversely, disruption of adhesion and polarity is thought to drive cancer progression. The mammary gland is an important model for cell adhesion due to its postnatal hormonally regulated development; ducts undergo branching morphogenesis in response to steroid hormones during puberty. These hormonal signals induce a transition from simple to stratified architecture, initiated by asymmetric luminal cell divisions. Ductal elongation is accomplished by this multilayered, low-polarity epithelium, and polarity is reestablished as elongation ceases. The requirement for cell adhesion has been tested in 3D culture and in vivo, using gene deletion, knockdown, and misexpression in both developmental and homeostatic contexts. Attention has focused on E-cadherin, the major classical cadherin in luminal epithelial cells. Classic studies revealed a requirement for E-cadherin during lactation, and E-cadherin loss is widely posited to promote metastasis. However, recent findings demonstrated a broader requirement for E-cadherin during branching morphogenesis and homeostasis and also, surprisingly, in epithelial dissemination. These studies suggest that long-standing models of the role of adhesion in epithelial biology need to be revisited. Advances in inducible gene expression and knockdown, CRISPR/Cas9 technology, and fluorescent labeling of genetically modified cells offer the opportunity to test the roles of diverse adhesion systems and to develop a mechanistic understanding of how cell adhesion regulates development and cancer.

Keywords: Branching morphogenesis; Breast cancer; Cadherin switch; E-cadherin; Epithelial–mesenchymal transition; Mammary epithelium; Metastasis; P-cadherin.

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Figures

Figure 1
Figure 1
Normal transitions in adhesion during epithelial branching morphogenesis. Mammary epithelium initiates branching morphogenesis postnatally. Tube elongation is accomplished by a stratified terminal end bud, which contains many internal luminal cells that lack apicobasal polarity and display reduced numbers of intercellular junctions. The epithelium at the rear polarizes to a bilayered, simple ductal architecture consisting of an inner layer of luminal cells and a basal layer of myoepithelial cells. Epithelial cells in the ducts are connected by many cell–cell junctions. Schematic adapted from original by Robert Huebner, with permission.
Figure 2
Figure 2
E-cadherin is required at multiple stages of mammary epithelial development. (A) Mammary pubertal branching morphogenesis initiates at approximately 3 weeks postnatal. A stratified terminal end bud (TEB) leads the elongation front, and a full ductal network forms over 7 weeks. During pregnancy, lactogenic hormones induce the ductal epithelium to form specialized structures called alveoli that mature to secrete milk during lactation. Different genetic approaches have been used to test the consequences of E-cadherin loss during distinct stages of development. (B) E-cadherin is required for branching morphogenesis (Shamir et al., 2014). E-cadherin− cells (green) within transplanted genetic mosaic epithelium are excluded from a ductal network elaborated exclusively by E-cadherin+ cells. (C) E-cadherin is required for maintenance of epithelial architecture (Shamir et al., 2014). E-cadherin− cells (green) are extruded apically and basally from mature E-cadherin+ epithelial ducts. (D) E-cadherin is required for terminal differentiation and cell survival of alveoli in the lactating gland (Boussadia et al., 2002). E-cadherin loss induces lobuloalveolar collapse and massive apoptosis.
Figure 3
Figure 3
E-cadherin is required for Twist1-induced single cell dissemination. 3D organotypic culture of primary mouse mammary epithelium was used to isolate the effects of single gene changes associated with the epithelial–mesenchymal transition. (A) In the assay, fragments of mammary ducts, called “organoids,” are explanted into a basement membrane-rich extracellular matrix. Genetic perturbations, including Cre-lox-based gene deletion, shRNA knockdown, and tet-inducible gene expression, are performed in vitro. (B) Normal organoids branch in response to growth factor. (C) E-cadherin deletion blocks branching and induces epithelial disorganization. (D) Twist1 expression blocks branching and induces single cell dissemination. (E) E-cadherin knockdown inhibits Twist1-induced single cell dissemination. Bars, 20 μm. Images ©Shamir et al. (2014). Originally published in The Journal of Cell Biology, doi: http://dx.doi.org/10.1083/jcb.201306088.
Figure 4
Figure 4
Is there are conserved epithelial migratory program? Dissemination might be explained by a switch in the substrate of migration from adjacent cells to ECM. (A) Epithelial cells collectively migrate as an elongating bud during mammary branching morphogenesis. Within the multilayer, an individual epithelial cell (green; dark gray shade in the print version) can appear elongated and protrusive. (B) During Twist1-induced dissemination, a single epithelial cell (green; dark gray shade in the print version) migrates through the ECM with amoeboid morphology and extensive protrusions at the leading front.
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