Transactivation of Vimentin by Beta-Catenin in Human Breast Cancer Cells

Abstract

The cytoplasmic and nuclear redistribution of β-catenin and the de novo expression of vimentin are frequently involved in the epithelial-to-mesenchymal transition associated with increased invasive/migratory properties of epithelial cells. Because β-catenin can act as a coactivator of transcription through its binding to the T-cell factor (TCF)/lymphoid enhancer factor 1 transcription factor family, we have explored the possibility that βcatenin/TCF could directly transactivate vimentin. We first compared vimentin expression in relation with the localization of β-catenin in eight breast cancer cell Unes displaying various degrees of invasiveness and in a model of cell migration using human mammary MCF10A cells. We could thus show a cytoplasmic and/or nuclear distribution of β -catenin in invasive/migratory cells expressing vimentin, but not in noninvasive/stationary vimentin-negative cell lines. In addition, the human vimentin promoter was found to be up-regulated by β-catenin and TCF-4 cotransfection. Varying with the cellular background, a diminution of this up-regulation was observed when the putative β -catenin/TCF binding site of the vimentin promoter was mutated. Our results therefore demonstrate that the vimentin promoter is a target of the β-catenin/TCF pathway and strongly suggest an implication of this regulation in epithelial cell migration/invasion.

Intestinal adenomagenesis involves core molecular signatures of the epithelial–mesenchymal transition

“…However, some neoplastic cells with strong cytoplasmic b-catenin staining were vimentin-negative. A previous study of cultured breast cancer cells has shown that vimentin can be directly transactivated by the accumulation and translocation of cytoplasmic b-catenin (Gilles et al 2003). Our study, by contrast, focuses on the early intestinal adenoma, in vivo.…”

The importance of the epithelial-mesenchymal transition in breast cancer

“…The fact that vimentin expression is a late event in EMT suggests a temporal sequence of gene regulation events in which the loss of epithelial features directly precedes and enables the upregulation of mesenchymal genes [19]. Direct activation of vimentin expression by β-catenin/T-cell factor/lymphocyte enhancer factor-1 has been demonstrated in human breast tumor cells [17], consistent with the activation of β-catenin as a downstream event ensuing from E-cadherin loss. More recently, ZEB2/SIP1 has been shown to indirectly promote vimentin expression during EMT in a β-catenin-independent manner [20], suggesting the existence of as yet unknown transactivators driving EMTassociated vimentin expression.…”

“…Nevertheless, elevated vimentin expression correlates well with increased cell migration, invasion, and EMT induction in several breast cancer cell lines [17] and is coordinately regulated together with other mesenchymal markers, such as the extracellular matrix molecule tenascin C [18]. Although the mechanisms underlying E-cadherin downregulation are fairly well documented, the molecular events that trigger vimentin expression during EMT are less well delineated.…”

Sulodexide alone or in combination with low doses of everolimus inhibits the hypoxia-mediated epithelial to mesenchymal transition in human renal proximal tubular cells

“…High concentrations of EVE, through a massive mTORC1 inhibition, lead to the downregulation of S6K and the subsequent hyper-activation of mTORC2 that, sustaining the phosphorylation of Akt at S473, induces a feedback loop that stimulates PI3K-Akt signaling activating the cellular/molecular machinery which leads to renal fibrosis [47][48][49][50]. In particular, it has been suggested that Akt, once activated, induces, through the inhibition of GSK3, the nuclear translocation of bcatenin which stimulates the expression of EMT-associated genes [51].…”