Until now the essential transcription factor that determines the epithelial 
phenotype of breast cancer has not been identified and its role in 
epithelial-to-mesenchymal transition (EMT) and tumor progression remain unclear. 
Here, by analyzing large expression profiles of human breast cancer cells, we 
found an extraordinary correlation between the expression of Grainyhead 
transcription factor Grhl2 and epithelial marker E-cadherin. Knockdown of Grhl2 
expression by shRNA in human mammary epithelial cell MCF10A leads to 
down-regulation of E-cadherin and EMT. Grhl2 is down-regulated in disseminated 
cancer cells that have undergone EMT, and over-expression of Grhl2 is sufficient 
to induce epithelial gene expression. Large clinical datasets reveal that 
expression of Grhl2 is significantly associated with poor relapse free survival 
and increased risk of metastasis in breast cancer patients. In mouse models, 
over-expression of Grhl2 significantly promotes tumor growth and metastasis. 
Further testing of several Grhl2 regulated genes leads to the same conclusions 
that the tumorigenic and metastatic potentials of tumor cells are linked to 
epithelial phenotype but not mesenchymal phenotype. In conclusion, our findings 
indicate that Grhl2 plays an essential role in the determination of epithelial 
phenotype of breast cancers, EMT and tumor progression.