The TGFβ2-Snail1-miRNATGFβ2 Circuitry is Critical for the Development of Aggressive Functions in Breast Cancer
Liyun Luo , Ning Xu , Weina Fan , Yixuan Wu , Pingping Chen , Zhihui Li , Zhimin He , Hao Liu , Ying Lin , Guopei Zheng
Clinical and Translational Medicine ›› 2024, Vol. 14 ›› Issue (2) : e1558
The TGFβ2-Snail1-miRNATGFβ2 Circuitry is Critical for the Development of Aggressive Functions in Breast Cancer
There have been contradictory reports on the biological role of transforming growth factor-βs (TGFβs) in breast cancer (BC), especially with regard to their ability to promote epithelial-mesenchymal transition (EMT). Here, we show that TGFβ2 is preferentially expressed in mesenchymal-like BCs and maintains the EMT phenotype, correlating with cancer stem cell-like characteristics, growth, metastasis and chemo-resistance and predicting worse clinical outcomes. However, this is only true in ERα− BC. In ERα+ luminal-type BC, estrogen receptor interacts with p-Smads to block TGFβ signalling. Furthermore, we also identify a microRNAs (miRNAs) signature (miRNAsTGFβ2) that is weakened in TGFβ2-overexpressing BC cells. We discover that TGFβ2-Snail1 recruits enhancer of zeste homolog-2 to convert miRNAsTGFβ2 promoters from an active to repressive chromatin configuration and then repress miRNAsTGFβ2 transcription, forming a negative feedback loop. On the other hand, miRNAsTGFβ2 overexpression reverses the mesenchymal-like traits in agreement with the inhibition of TGFβ2-Snail1 signalling in BC cells. These findings clarify the roles of TGFβ2 in BC and suggest novel therapeutic strategies based on the TGFβ2-Snail1-miRNAsTGFβ2 loop for a subset type of human BCs.
breast cancer / chromatin configuration / epithelial-mesenchymal transition / miRNAs / TGFβ2
2024 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.
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