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

Rong Fu, Chen-Feng Han, Ting Ni, Lei Di, Li-Juan Liu, Wen-Cong Lv, Yan-Ran Bi, Nan Jiang, Yin He, Hong-Mei Li, Shui Wang, Hui Xie, Bao-An Chen, Xiao-Sheng Wang, Stephen J. Weiss, Tao Lu, Qing-Long Guo and Zhao-Qiu Wu ()
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Rong Fu: China Pharmaceutical University
Chen-Feng Han: China Pharmaceutical University
Ting Ni: China Pharmaceutical University
Lei Di: China Pharmaceutical University
Li-Juan Liu: China Pharmaceutical University
Wen-Cong Lv: China Pharmaceutical University
Yan-Ran Bi: China Pharmaceutical University
Nan Jiang: China Pharmaceutical University
Yin He: China Pharmaceutical University
Hong-Mei Li: China Pharmaceutical University
Shui Wang: Nanjing Medical University
Hui Xie: Nanjing Medical University
Bao-An Chen: Southeast University
Xiao-Sheng Wang: China Pharmaceutical University
Stephen J. Weiss: University of Michigan
Tao Lu: China Pharmaceutical University
Qing-Long Guo: China Pharmaceutical University
Zhao-Qiu Wu: China Pharmaceutical University

Nature Communications, 2019, vol. 10, issue 1, 1-18

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11278-7

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