Cell Polarity in Motion: Redefining Mammary Tissue Organization Through EMT and Cell Polarity Transitions

Abstract

Epithelial to mesenchymal transition (EMT) and its reversion via mesenchymal to epithelial transition (MET), represent a stepwise cycle of epithelial plasticity that allows for normal tissue remodelling and diversification during development. In particular, epithelial-mesenchymal plasticity is central to many aspects of mammary development and has been proposed to be a key process in breast cancer progression. Such epithelial-mesenchymal plasticity requires complex cellular reprogramming to orchestrate a change in cell shape to an alternate morphology more conducive to migration. During this process, epithelial characteristics, including apical-basal polarity and specialised cell-cell junctions are lost and mesenchymal properties, such as a front-rear polarity associated with weak cell-cell contacts, increased motility, resistance to apoptosis and invasiveness are gained. The ability of epithelial cells to undergo transitions through cell polarity states is a central feature of epithelial-mesenchymal plasticity. These cell polarity states comprise a set of distinct asymmetric distributions of cellular constituents that are fashioned to allow specialized cellular functions, such as the regulated homeostasis of molecules across epithelial barriers, cell migration or cell diversification via asymmetric cell divisions. Each polarity state is engineered using a molecular toolbox that is highly conserved between organisms and cell types which can direct the initiation, establishment and continued maintenance of each asymmetry. Here we discuss how EMT pathways target cell polarity mediators, and how this EMT-dependent change in polarity states impact on the various stages of breast cancer. Emerging evidence places cell polarity at the interface of proliferation and morphology control and as such the changing dynamics within polarity networks play a critical role in normal mammary gland development and breast cancer progression.

Epithelial-mesenchymal transition during extravillous trophoblast differentiation

“…34 In these biological contexts, EGF acts as an inducer of EMT signaling pathways through its regulatory effects on transcription factors and their downstream target genes. 9 EGF and EGFR1 are localized in the syncytiotrophoblast and the cytotrophoblast. 35 EGF expression is most pronounced in the first trimester placenta and is reduced closer to term, suggesting an association of EGF with the early stages of placental development.…”

Mechanisms that link the oncogenic epithelial–mesenchymal transition to suppression of anoikis

“…Epithelial cell polarity is compromised during oncogenic EMT through diverse transcriptional and signaling effects (Godde et al, 2010;Moreno-Bueno et al, 2008;Xu et al, 2009). Three polarity complexes, crumbs, Par and scribble, contribute to polarity in normal epithelial cells and aberrations in each of these affect tumor progression (Ellenbroek et al, 2012).…”

The ubiquitin ligase Smurf2 suppresses TGFβ-induced epithelial–mesenchymal transition in a sumoylation-regulated manner

“…Importantly, EMT disrupts the acinar morphology that manifests as filling of the hollow centers, outward invasiveness, and dysregulation of the abundance or localization of the epithelial marker protein E-cadherin. 38,[40][41][42][43] To determine the role of Smurf2 in EMT, we induced the knockdown of Smurf2 by RNA interference (RNAi) in NMuMG cells using transient transfection. Short hairpin RNAs (shRNAs) targeted against two distinct regions within Smurf2, alone or together, robustly downregulated exogenous Smurf2 in 293T cells and NMuMG mammary epithelial cells (Supplementary Figures S1A and B).…”