The TGFβ2-Snail1-miRNA_TGFβ2 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 (miRNAs_TGFβ2 ) 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 miRNAs_TGFβ2 transcription, forming a negative feedback loop. On the other hand, miRNAs_TGFβ2 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-miRNAs_TGFβ2 loop for a subset type of human BCs.