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.

αB-Crystallin Regulates Subretinal Fibrosis by Modulation of Epithelial-Mesenchymal Transition

“…Thus, when the epithelial phenotype is maintained with adherent junctions, the cells will not be affected by the action of stimuli triggering EMT. 31 These findings might elucidate the mechanism of the absence of aB-crystallin silencing effect on EMT markers in the physiological RPE cells. Our results indicate that aB-crystallin inhibition can affect only RPE cells that have lost cadherin-mediated adhesions, but it does not influence the cellular phenotypes of the normal RPE monolayer.…”

Akt2 interacts with Snail1 in the E-cadherin promoter

“…Surprisingly, part of Akt activation by Snail1 is independent of Snail1 repressive activity, as a Snail1 mutant unable to recruit co-repressors stimulated Akt kinase activity, although to a lower extent than the wild-type protein (see Figure 1). This mutant, P2A, does not bind to the different cofactors necessary for repression of CDH1 or PTEN (Escriva`et al, 2008, Garcı´a de Herreros et al, 2010. These experiments indicated that, although part of the Akt activation by Snail1 is consequence of repression of Figure 6 Akt2 increases histone H3 phosphorylation in Thr45 and binding of P-Thr45 H3 to the CDH1 promoter.…”

“…For instance, Akt1 overexpression induces EMT, increasing the expression of the Snail1 transcriptional factor and other E-cadherin repressors (Julien et al, 2007). Snail1 upregulation is a consequence of increased transcription and enhanced protein stability as Akt controls both processes (Garcı´a de Herreros et al, 2010). Akt proteins are also important downstream effectors of Snail1 and are …”

“…Although the role of this factor in triggering EMT and repressing CDH1 expression is well established, its contribution to CDH1 silencing is variable, as CDH1 is also controlled by Zeb proteins. These transcriptional factors require Snail1 for their induction but not for sustained expression (Garcı´a de Herreros et al, 2010). Differently to this pro-mesenchymal action of Akt2, Akt1 might have a more complex role as, in addition to the pro-epithelial effects, it also contributes to Snail1 expression, acting both on gene expression and protein stabilization (see above, and also Supplementary Figure 2).…”

“…Moreover, ectopic expression of Snail1 promotes an EMT in epithelial tumor cell lines (Batlle et al, 2000;Cano et al, 2000), characterized by decreased expression of epithelial genes, such as E-cadherin, and upregulation of mesenchymal genes. Repression of epithelial genes by Snail1 requires the binding of the C-terminal domain of this protein to 5 0 -CACCTG-3 0 elements present in these promoters and the interaction of the SNAG Snail1 sequence with co-repressors (Thiery et al, 2009;Garcı´a de Herreros et al, 2010). Conversely, activation of mesenchymal genes (fibronectin, vimentin) is thought to be a more indirect effect, partially dependent on Ecadherin downregulation, and requiring stimulation of several transduction pathways, such as those involving extracellular signal-regulated kinase-2 (ERK2), Sp1/Ets-1, nuclear factor-kB and b-catenin (Ohkubo and Ozawa 2003;Jorda`et al, 2005Jorda`et al, , 2007Solanas et al, 2008;Stemmer et al, 2008).…”