Epithelial to mesenchymal transition (EMT) facilitates tissue remodelling during embryonic development and is viewed as an essential early step in tumour metastasis. We found that all five members of the microRNA-200 family (miR-200a, miR-200b, miR-200c, miR-141 and miR-429) and miR-205 were markedly downregulated in cells that had undergone EMT in response to transforming growth factor (TGF)- or to ectopic expression of the protein tyrosine phosphatase Pez. Enforced expression of the miR-200 family alone was sufficient to prevent TGF--induced EMT. Together, these microRNAs cooperatively regulate expression of the E-cadherin transcriptional repressors ZEB1 (also known as EF1) and SIP1 (also known as ZEB2), factors previously implicated in EMT and tumour metastasis. Inhibition of the microRNAs was sufficient to induce EMT in a process requiring upregulation of ZEB1 and/or SIP1. Conversely, ectopic expression of these microRNAs in mesenchymal cells initiated mesenchymal to epithelial transition (MET). Consistent with their role in regulating EMT, expression of these microRNAs was found to be lost in invasive breast cancer cell lines with mesenchymal phenotype. Expression of the miR-200 family was also lost in regions of metaplastic breast cancer specimens lacking E-cadherin. These data suggest that downregulation of the microRNAs may be an important step in tumour progression.

1. Hanson Institute and Division of Human Immunology, Institute of Medical and Veterinary Science, Adelaide, SA 5000, Australia.
2. Discipline of Paediatrics, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide SA 5005 and Women's and Children's Health Research Institute, Adelaide, SA 5006, Australia.
3. Division of Tissue Pathology, Institute of Medical and Veterinary Science, Adelaide, SA 5000, Australia.
4. Discipline of Medicine, The University of Adelaide, Adelaide, SA 5005, Australia.
5. School of Molecular and Biomedical Sciences, The University of Adelaide, Adelaide, SA 5005, Australia.
6. Current address, Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney, Newtown, NSW 2042, Australia.
7. These authors contributed equally to this study.

Correspondence to: Gregory J. Goodall^1,4,7 e-mail: greg.goodall@imvs.sa.gov.au

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