Snail family regulation and epithelial mesenchymal transitions in breast cancer progression

Abstract

Since its initial description, the interconversion between epithelial and mesenchymal cells (designed as epithelial-mesenchymal or mesenchymal-epithelial transition, EMT or MET, respectively) has received special attention since it provides epithelial cells with migratory features. Different studies using cell lines have identified cytokines, intercellular signaling elements and transcriptional factors capable of regulating this process. Particularly, the identification of Snail family members as key effectors of EMT has opened new ways for the study of this cellular process. In this article we discuss the molecular pathways that control EMT, showing a very tight and interdependent regulation. We also analyze the contribution of EMT and Snail genes in the process of tumorigenesis using the mammary gland as cellular model.

Figure 1. Structure of Snail protein

The figure shows a diagram depicting the different domains of Snail protein and the interactors binding to each of them. Phosphorylation sites are indicated as dots: black, if they stimulate Snail action; red, if they inhibit it. The arrow initiating at LOX protein labels the Snail1 amino acids putatively modified by this enzyme.

Figure 2. Self-regulation of Snail expression

In epithelial cells with high adherens junction-mediated adhesion (left), E-cadherin blocks NF-κB activation and translocation to the nucleus. Stimuli, such as TGF-β, inducing SNAIL gene transcription are limited by the inhibitory loop created by Snail protein that binds to SNAIL and EGR1 promoters, down-regulating SNAIL promoter activity. In cells with lower E-cadherin activity (right), Snail induction as consequence of the action of TGF-β or additional signals enhances NF-κB translocation to the nucleus and the stimulation of mesenchymal genes, among them Snail itself. This stimulatory loop is further stimulated by the inhibition of E-cadherin that enables more NF-κB activation. Consequently, Snail expression is temporarily extended favoring the repression of epithelial genes. Some of these Snail target proteins or miRNAs might act like E-cadherin, repressing mesenchymal genes. Moreover NF-κB might also stimulate the synthesis of additional repressors of E-cadherin, providing additional points of crosstalk between the two pathways.

Figure 3. EMT activation during breast carcinoma progression and metastasis

Following tumor initiation, a local microenvironment evolves towards the emergence of a tumor mass, resulting in oncogenic pathways activation, local hypoxia conditions, inflammatory conditions and stroma reaction. These events independently converge to activate EMT to some extent, linked to apoptotic resistance and functional stemness, The EMT intensity is reflected by the invasion mode, allowing cohesive migration or individual cell migration. These processes directly contribute to carcinoma progression and metastasis.