A ZEB1/p53 signaling axis in stromal fibroblasts promotes mammary epithelial tumours

Abstract

Accumulating evidence indicates that the zinc-finger transcription factor ZEB1 is predominantly expressed in the stroma of several tumours. However, the role of stromal ZEB1 in tumour progression remains unexplored. In this study, while interrogating human databases, we uncover a remarkable decrease in relapse-free survival of breast cancer patients expressing high ZEB1 levels in the stroma. Using a mouse model of breast cancer, we show that ZEB1 inactivation in stromal fibroblasts suppresses tumour initiation, progression and metastasis. We associate this with reduced extracellular matrix remodeling, immune cell infiltration and decreased angiogenesis. ZEB1 deletion in stromal fibroblasts increases acetylation, expression and recruitment of p53 to FGF2/7 , VEGF and IL6 promoters, thereby reducing their production and secretion into the surrounding stroma. Importantly, p53 ablation in ZEB1 stroma-deleted mammary tumours sufficiently recovers the impaired cancer growth and progression. Our findings identify the ZEB1/p53 axis as a stroma-specific signaling pathway that promotes mammary epithelial tumours.

Endothelial ZEB1 promotes angiogenesis-dependent bone formation and reverses osteoporosis

“…2h). These findings are consistent with previous reports demonstrating that ZEB1 is positively associated with VEGFA expression in cancer cells 20 and cancer-associated fibroblasts 15 . Microphil-perfused angiography demonstrated a markedly reduced vessel number and volume in the metaphysis of 3-weekold Zeb1 ΔEC tibia (Fig.…”

“…1a; ref. 15 ) and crossed with Tie2-Cre 16,17 transgenic line to generate Tie2-Cre − ;Zeb1 fl/fl control and Tie2-Cre + ;Zeb1 fl/fl EC-specific ZEB1 knockout mice (designated Zeb1 WT and Zeb1 ΔEC mice, respectively). In addition, Zeb1 fl/fl mice were also mated with Cdh5(PAC)-CreERT2 18 transgenic line and the resulting Cdh5(PAC)-CreERT2 -;Zeb1 fl/fl and Cdh5(PAC)-CreERT2 + ;Zeb1 fl/fl mice were treated with tamoxifen to generate control and EC-specific ZEB1 knockout mice (designated Zeb1 WT and Zeb1 iΔEC mice, respectively).…”

“…Mice were housed under standard specific-pathogen-free conditions and all animal experiments were performed in accordance with protocols that were approved and authorized by the Animal Welfare and Ethics Committee of China Pharmaceutical University. Mice carrying Zeb1 (exon 3) floxed alleles (Zeb1 fl/fl ) were generated in our laboratory and have been described previously 15 . Tie2-Cre transgenic mice were purchased from Jackson Laboratory (#008863).…”

Oncogenic functions of the EMT-related transcription factor ZEB1 in breast cancer

“…The transformed tumor cells with high ZEB1 levels lost their epithelial characteristics, developed a mesenchymal/motile phenotype, and subsequently invaded into lymph or blood vessels. When metastatic breast cancer was formed in a distant location, the ZEB1 expression level was decreased to promote the expression of the epithelial marker E-cadherin and inhibit the expression of the mesenchymal marker Vimentin, occurring the mesenchymal-epithelial transition (MET) process to recover the epithelial features and lose the mesenchymal/motile phenotype with a low ZEB1 level in stromal fibroblasts to promote mammary epithelial tumors, which demonstrated the high expression and activation of ZEB1 in the stroma was associated with increased ECM remodeling, immune cell infiltration and angiogenesis through increasing FGF2/7, VEGF and IL-6 expression and secretion into the surrounding stroma [79]. Tumor vascularization predicted the deprivation of nutrients and oxygen and facilitated the metastasis process of tumor cells through vessel formation with or without endothelial transdifferentiation.…”

Dynamic Expression Profiles of β-Catenin during Murine Cardiac Valve Development

“…Phosphorylation at Ser552 induces β-catenin accumulation in the nucleus and increases its transcriptional activity [ 59 , 60 , 61 ]. The specificities of these antibodies were validated as recognizing the appropriate epitopes in various model systems, including knockout animals and cell lines [ 57 , 61 , 62 , 63 , 64 , 65 ]. IHC staining for both activated (β-catenin pS552 ) and membrane β-catenin revealed dynamic staining patterns that are spatially and temporally regulated during embryonic gestation.…”