The TGFß2-Snail1-miRNATGFß2 Circuitry is Critical for the Development of Aggressive Functions in Breast Cancer.

ABSTRACT

There have been contradictory reports on the biological role of transforming growth factor-ßs (TGFßs) in breast cancer (BC), especially with regard to their ability to promote epithelial-mesenchymal transition (EMT). Here, we show that TGFß2 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 TGFß signalling. Furthermore, we also identify a microRNAs (miRNAs) signature (miRNAsTGFß2 ) that is weakened in TGFß2-overexpressing BC cells. We discover that TGFß2-Snail1 recruits enhancer of zeste homolog-2 to convert miRNAsTGFß2 promoters from an active to repressive chromatin configuration and then repress miRNAsTGFß2 transcription, forming a negative feedback loop. On the other hand, miRNAsTGFß2 overexpression reverses the mesenchymal-like traits in agreement with the inhibition of TGFß2-Snail1 signalling in BC cells. These findings clarify the roles of TGFß2 in BC and suggest novel therapeutic strategies based on the TGFß2-Snail1-miRNAsTGFß2 loop for a subset type of human BCs.