DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells

Eger, Andreas; Aigner, Karl Reinhard; Sonderegger, Stefan Eugen; Dampier, Brigitta; Oehler, Susanne; Schreiber, Martin; Berx, Geert; Cano, Amparo; Beug, Hartmut; Foisner, Roland

doi:10.1038/sj.onc.1208429

Cited by 707 publications

(619 citation statements)

References 56 publications

(67 reference statements)

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“…In agreement with these studies, we also found that Snail and Slug mRNA levels were upregulated in our EMT tumors. In addition, we also detected an increase in transcript levels of Zeb1 and Twist, both of which have been shown to directly repress E-cadherin transcription and induce EMT in breast cancer cells in vitro (Eger et al, 2005;Vesuna et al, 2008). Whether Zeb1 and Twist are causally linked to tumor recurrence in a similar manner to Snail will require further investigation.…”

Section: Discussionmentioning

confidence: 72%

Reversibility and recurrence of IGF-IR-induced mammary tumors

et al. 2009

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Section: Discussionmentioning

confidence: 72%

Reversibility and recurrence of IGF-IR-induced mammary tumors

et al. 2009

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“…Decreased Zeb2 mRNA was observed using five independent Zeb1 shRNAs (Supplementary Figure S9b). Conversely, EpH4-FosER cells expressing ZEB1 40 had increased Zeb2 mRNA in the absence of 4-hydroxyTamoxifen ( Supplementary Figures S9c and d). This indicates that Zeb1 contributes to controlling Zeb2 expression in EpH4-derived cells.…”

Section: Resultsmentioning

confidence: 99%

“…13,14 Ras and TGFβ cooperate to induce and stabilize a mesenchymal switch in EpH4 cells. 21,22,40 Unlike human breast cancer cells where upstream signalling kinases activation is required, 14,16 ectopic Fra-1 expression was sufficient for EMT and tumorigenesis in EpH4 cells. Moreover, Fra-1 increased TGFβ expression and production, similarly to c-Fos and unlike oncogenic Ras, 43 thus TGFβ treatment was not necessary for EMT in EpFra1 cells.…”

Section: Discussionmentioning

confidence: 99%

“…The origin, cultivation and properties of EpH4, EpRas and EpRasXT and EpGFP and EpdEF1GFP cells have been previously described. 22,40,47 NMuMG cells and cultivation conditions were obtained from ATCC (Barcelona, Spain). EpFra1, EpRas NMuMG-GFP and NMuMG-Fra1ER cells were generated by retroviral gene transfer as described in Bakiri et al, 48 using pBabeFra1, pBabeGFP or pBabeFra1ER retroviral plasmids.…”

Section: Methodsmentioning

confidence: 99%

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Fra-1/AP-1 induces EMT in mammary epithelial cells by modulating Zeb1/2 and TGFβ expression

et al. 2014

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Epithelial-to-mesenchymal transition (EMT) is essential for embryonic morphogenesis and wound healing and critical for tumour cell invasion and dissemination. The AP-1 transcription factor Fra-1 has been implicated in tumorigenesis and in tumour-associated EMT in human breast cancer. We observed a significant inverse correlation between Fra-1 mRNA expression and distant-metastasis-free survival in a large cohort of breast cancer patients derived from multiple array data sets. This unique correlation among Fos genes prompted us to assess the evolutionary conservation between Fra-1 functions in EMT of human and mouse cells. Ectopic expression of Fra-1 in fully polarized, non-tumourigenic, mouse mammary epithelial EpH4 cells induced a mesenchymal phenotype, characterized by a loss of epithelial and gain of mesenchymal markers. Proliferation, motility and invasiveness were also increased in the resulting EpFra1 cells, and the cells were tumourigenic and efficiently colonized the lung upon transplantation. Molecular analyses revealed increased expression of Tgfβ1 and the EMT-inducing transcription factors Zeb1, Zeb2 and Slug. Mechanistically, Fra-1 binds to the tgfb1 and zeb2 promoters and to an evolutionarily conserved region in the first intron of zeb1. Furthermore, increased activity of a zeb2 promoter reporter was detected in EpFra1 cells and shown to depend on AP-1-binding sites. Inhibiting TGFβ signalling in EpFra1 cells moderately increased the expression of epithelial markers, whereas silencing of zeb1 or zeb2 restored the epithelial phenotype and decreased migration in vitro and tumorigenesis in vivo. Thus Fra-1 induces changes in the expression of genes encoding EMT-related transcription factors leading to the acquisition of mesenchymal, invasive and tumorigenic capacities by epithelial cells. This study defines a novel function of Fra-1/AP-1 in modulating tgfb1, zeb1 and zeb2 expression through direct binding to genomic regulatory regions, which establishes a basis for future in vivo genetic manipulations and preclinical studies using mouse models. Epithelial-to-mesenchymal transition (EMT) is a complex biological programme that occurs in physiological processes during embryonic development and wound healing as well as in pathological conditions, such as organ fibrosis and carcinogenesis. During EMT, cells lose epithelial features and acquire mesenchymal characteristics. The acquisition of a mesenchymal state by malignant cancer cells is associated with decreased cell-cell adhesion, and increased migratory and invasive properties, which are crucial for metastasis. [1][2][3][4][5] The adherens junction (AJ) protein E-cadherin, encoded by cdh1, is a central determinant of the epithelial state and its downregulation is the hallmark of EMT. A number of molecular pathways converging on E-cadherin have been implicated in EMT. Transcription factors (TF) of the Snail, Zeb and Twist families, initially identified as regulators of epithelialmesenchymal plasticity during morphogenesis were shown to orchestrate EMT by...

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“…Zinc finger E‐box binding protein 1 (ZEB1) and ZEB2 (also known as δEF‐1 and SIP‐1, respectively) are well‐known transcriptional regulators that induce EMT, which plays important roles in both normal physiological and pathological processes (Eger et al ., 2005; Vandewalle et al ., 2005; Zhang et al ., 2015). While ZEB1 and ZEB2 have many similar properties in transcriptional regulation, they are different in their expression profiles, some molecular and biological functions, including regulation of cell differentiation and disease progression (Postigo and Dean, 2000; Wakamatsu et al ., 2001).…”

Section: Introductionmentioning

confidence: 99%

ZEB1‐regulated inflammatory phenotype in breast cancer cells

et al. 2017

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Zinc finger E‐box binding protein 1 (ZEB1) and ZEB2 induce epithelial‐mesenchymal transition (EMT) and enhance cancer progression. However, the global view of transcriptional regulation by ZEB1 and ZEB2 is yet to be elucidated. Here, we identified a ZEB1‐regulated inflammatory phenotype in breast cancer cells using chromatin immunoprecipitation sequencing and RNA sequencing, followed by gene set enrichment analysis (GSEA) of ZEB1‐bound genes. Knockdown of ZEB1 and/or ZEB2 resulted in the downregulation of genes encoding inflammatory cytokines related to poor prognosis in patients with cancer, including IL6 and IL8, therefore suggesting that ZEB1 and ZEB2 have similar functions in terms of the regulation of production of inflammatory cytokines. Antibody array and ELISA experiments confirmed that ZEB1 controlled the production of the IL‐6 and IL‐8 proteins. The secretory proteins regulated by ZEB1 enhanced breast cancer cell proliferation and tumor growth. ZEB1 expression in breast cancer cells also affected the growth of fibroblasts in cell culture, and the accumulation of myeloid‐derived suppressor cells in tumors in vivo. These findings provide insight into the role of ZEB1 in the progression of cancer, mediated by inflammatory cytokines, along with the initiation of EMT.

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DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells

Cited by 707 publications

References 56 publications

Reversibility and recurrence of IGF-IR-induced mammary tumors

Reversibility and recurrence of IGF-IR-induced mammary tumors

Fra-1/AP-1 induces EMT in mammary epithelial cells by modulating Zeb1/2 and TGFβ expression

ZEB1‐regulated inflammatory phenotype in breast cancer cells

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