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.
Highlights
Accumulating evidence indicates that the zinc-finger transcription factor ZEB1 is predominantly expressed in the stroma of several tumours
To determine the expression pattern of ZEB1 in different subtypes of human breast cancer, we performed immunostaining of ZEB1 in the tissue arrays consisting of 98 luminal (ER and/or PR positive, HER2 negative or positive), 22 HER2+ (ER and PR negative, HER2 positive) and 47 triple-negative breast cancer (TNBC; ER and PR negative, HER2 negative) tumour samples, as well as the matched normal samples
We found that ZEB1 protein was primarily present in the stromal compartment, but was largely absent in the epithelial compartment of luminal, HER2+ and TNBC tumours (Fig. 1a)
Summary
Stromal ZEB1 levels are increased in breast tumours. To determine the expression pattern of ZEB1 in different subtypes of human breast cancer, we performed immunostaining of ZEB1 in the tissue arrays consisting of 98 luminal (ER and/or PR positive, HER2 negative or positive), 22 HER2+ (ER and PR negative, HER2 positive) and 47 triple-negative breast cancer (TNBC; ER and PR negative, HER2 negative) tumour samples, as well as the matched normal samples. ZEB1 functions as a p53 inhibitor in stromal CAFs. Because the tumour suppressor p53 has been reported to play a critical role in controlling stromal and carcinoma cells expansion during tumour initiation and progression[31,32], we sought to determine whether ZEB1 deletion could affect the p53 expression level in stromal CAFs. Immunofluorescence analysis illustrated that p53 protein was barely detected in PyMT-Fib-WT mammary tumours, whereas its levels were dramatically increased in both stromal and epithelial compartments of PyMT-Fib-cKO tumours (Fig. 6a, b). Consistent with these observations, both the markedly reduced growth and proliferative activity of PyMT-Fib-ZEB1-cKO tumours were dramatically reversed following p53 excision (Fig. 8h–k) Taken together, these findings identify p53 as a functionally critical ZEB1 target in vivo, and suggest that the stromal ZEB1/p53 axis plays a critical role in controlling mammary tumour growth and progression in a paracrine fashion
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