Transcription factor slug-upregulated microRNA-221 suppresses E-cadherin expression and promotes breast cancer progression (TUM10P.1031)

Abstract

Abstract E-cadherin protein expression is blocked during tumorigenesis due to slug/snail-mediated suppression of E-cadherin transcription. However, this mechanism of transcriptional blockade cannot explain why metastatic breast cancer cells maintain very low level of E-cadherin even with E-cadherin mRNA overexpression. In the present study, we reveal that E-cadherin is also post-transcriptionally regulated by slug-promoted microRNA-221 (miR-221), which serves as an additional lock preventing E-cadherin expression in metastatic cancer cells. Profiling the predicted E-cadherin-targeting miRNAs in breast cancer tissues and cell lines treated with/without TGFβ shows that the miR-221 level is significantly higher in metastatic breast cancer tissues and in MDA-MB-231 cells compared with the cancer-adjacent normal tissues or non-metastatic MCF-7 cells, and that miR-221 level is subjected to the TGFβ regulation. The level of miR-221 is inversely correlated with E-cadherin expression in breast cancer cells, and experimentally depleting or elevating miR-221 induces or decreases E-cadherin expression, consequently promoting or suppressing breast cancer progression. Moreover, we found that miR-221 suppresses E-cadherin translation via binding to the open reading frame of the E-cadherin mRNA and that miR-221 is specifically upregulated by Slug. In conclusion, our results demonstrate for the first time that Slug-upregulated miR-221 promotes breast cancer via targeting E-cadherin.