The TGFβ2‐Snail1‐miRNATGFβ2 Circuitry is Critical for the Development of Aggressive Functions in Breast Cancer

• Published in: Clinical and translational medicine Vol. 14; no. 2; pp. e1558 - n/a
• Main Authors: Luo, Liyun, Xu, Ning, Fan, Weina, Wu, Yixuan, Chen, Pingping, Li, Zhihui, He, Zhimin, Liu, Hao, Lin, Ying, Zheng, Guopei
• Format: Journal Article
• Language: English
• Published: Heidelberg John Wiley & Sons, Inc 01.02.2024; John Wiley and Sons Inc; Wiley
• Subjects: Breast cancer; Breast surgery; Cancer therapies; Cell growth; Chemotherapy; chromatin configuration; epithelial‐mesenchymal transition; Kinases; Medical research; Metastasis; MicroRNAs; miRNAs; Patients; Polymerase chain reaction; Proteins; TGFβ2; Transcription factors; Tumors
• ISSN: 2001-1326; 2001-1326
• DOI: 10.1002/ctm2.1558

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. TGFβ2 was the major isoform overexpressed in TNBC. TGFβ2 maintains the EMT and aggressive phenotype of TNBC. ERα interacts with p‐Smads to block TGFβ signaling. Snail1 recruits EZH2 to repress miRNAs targeting TGFβ2.