Abstract
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.
Highlights
Epithelial-to-mesenchymal transition (EMT) has been demonstrated to play a critical role during tumor metastasis [1], which generates cells with migratory and invasive properties that are able to disseminate to distant organs [1,2]
We demonstrate that Grhl2 is the epithelial specific transcription factor that determines the epithelial phenotype of breast cancers, and plays a critical role in tumor progression
After injection into the mammary fat pad, 4T1 tumors spontaneously metastasize in a short period to distant organs, such as lung. 4T1 cancer cells can be recovered from lung about three weeks after injecting the tumor
Summary
Epithelial-to-mesenchymal transition (EMT) has been demonstrated to play a critical role during tumor metastasis [1], which generates cells with migratory and invasive properties that are able to disseminate to distant organs [1,2]. During the EMT process, transcription factors play crucial roles. Many signaling pathways that trigger cancer cells to undergo EMT converge at a group of transcription factors, including Snai, Snai, Zeb, Zeb, and Twist1 [4,5]. These transcription factors suppress E-cadherin and other epithelial specific genes directly or indirectly
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