Grhl2 Determines the Epithelial Phenotype of Breast Cancers and Promotes Tumor Progression

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.

Integrative Bioinformatics Analysis Reveals New Prognostic Biomarkers of Clear Cell Renal Cell Carcinoma

“…The role of GRHL2 downregulation in ccRCC has not been investigated, but its target, ZEB1, which is a direct suppressor of GRHL2, is overexpressed in kidney cancer. The GRHL2 targets miR-200a and-b are underexpressed in ccRCC samples (29 ), which supports the role of GRHL2 in ccRCC. These, and GRHL2 being a top-layer gene in the network, suggest that restoring of the function of GRHL2 (including its downstream targets) may be a new, potentially therapeutic direction in addition to being a potential diagnostic marker.…”

Induction of entosis by epithelial cadherin expression

“…Entosis is another mechanism by which the expression of E-cadherin limits transformed growth by inducing cell death. However, many breast tumors including the most invasive ductal carcinomas and metastatic tumors retain E-cadherin expression, and E-cadherin may promote tumor progression by supporting cell survival, collective modes of invasion, or the outgrowth of metastatic tumors that may be promoted by an epithelial rather than mesenchymal phenotype [19,[33][34][35][36][37][38][39]. Like E-cadherin, P-cadherin is also expressed in some breast cancers and is a poor prognostic indicator [20].…”

Downregulation of GRHL2 inhibits the proliferation of colorectal cancer cells by targeting ZEB1

“…Knockdown of GRHL2 in the human mammary epithelial cell line MCF10A leads to downregulation of E-cadherin. 16 GRHL2 is downregulated during epithelial-mesenchymal transition with kinetics similar to the loss of E-cadherin.…”

“…13,14 However, increasing evidence indicates that GRHL2 may have an oncogenic role in cancer development. [15][16][17][18] These controversial results suggest that the role of GRHL2 is possibly tumor-specific and highly dependent on its targets in different cancer cells. 19 However, the expression of GRHL2 in CRC is unknown and its role in CRC progression is also elusive.…”