Transcriptomics

Dataset Information

3

Dual Roles of the Transcription Factor Grainyhead-like 2 (GRHL2) in Breast Cancer


ABSTRACT: Using a retrovirus-mediated cDNA expression cloning approach we identified the grainyhead-like 2 (GRHL2) transcription factor as novel protooncogene. Overexpression of GRHL2 in NIH3T3 cells induced striking morphological changes, an increase in cell proliferation, anchorage-independent growth, and tumor growth in vivo. By combining a microarray analysis and a phylogenetic footprinting analysis with various biochemical assays we identified the epidermal growth factor receptor family member Erbb3 as a novel GRHL2 target gene. In breast cancer cell lines, shRNA-mediated knockdown of GRHL2 expression or functional inactivation of GRHL2 using dominant-negative GRHL2 proteins induce downregulation of ERBB3 gene expression, a striking reduction in cell proliferation and morphological and phenotypical alterations characteristic of an epithelial-to-mesenchymal transition (EMT), thus implying dual roles of GRHL2 in breast carcinogenesis. Interestingly, we could further demonstrate that expression of GRHL2 is directly suppressed by the transcription factor zinc-finger-enhancer binding protein 1 (ZEB1) which in turn is a direct target for repression by GRHL2, suggesting that the EMT transcription factors GRHL2 and ZEB1 form a double negative regulatory feedback loop in breast cancer cells. Finally, a comprehensive immunohistochemical analysis of GRHL2 expression in primary breast cancers showed loss of GRHL2 expression at the invasive front of primary tumors. A pathophysiological relevance of GRHL2 in breast cancer metastasis is further demonstrated by our finding of a statistically significant association between loss of GRHL2 expression in primary breast cancers and lymph-node metastasis. We thus demonstrate a crucial role of GRHL2 in breast carcinogenesis. To evaluate the role of the GRHL2 transcription factor in carcinogenessis we overexpressed the human GRHL2 protein in NIH3T3 cells. Parental NIH3T3 cells do not express the orthologic protein. Alterations in genome-wide transcriptional profiles were determined by microarray analysis.

ORGANISM(S): Mus musculus  

SUBMITTER: Stefan Werner   Christian Schulze  Luigi Terracciano  Malik Alawi  Volker Assmann  Sabrina Frey  Sabine Riethdorf  Guido Sauter  Lea Kling  Udo Schumacher  Vida Vafaizadeh  Klaus Pantel 

PROVIDER: E-GEOD-43610 | ArrayExpress | 2013-09-05

SECONDARY ACCESSION(S): GSE43610PRJNA186816

REPOSITORIES: GEO, ArrayExpress

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Dual roles of the transcription factor grainyhead-like 2 (GRHL2) in breast cancer.

Werner Stefan S   Frey Sabrina S   Riethdorf Sabine S   Schulze Christian C   Alawi Malik M   Kling Lea L   Vafaizadeh Vida V   Sauter Guido G   Terracciano Luigi L   Schumacher Udo U   Pantel Klaus K   Assmann Volker V  

The Journal of biological chemistry 20130629 32


Using a retrovirus-mediated cDNA expression cloning approach, we identified the grainyhead-like 2 (GRHL2) transcription factor as novel protooncogene. Overexpression of GRHL2 in NIH3T3 cells induced striking morphological changes, an increase in cell proliferation, anchorage-independent growth, and tumor growth in vivo. By combining a microarray analysis and a phylogenetic footprinting analysis with various biochemical assays, we identified the epidermal growth factor receptor family member Erbb  ...[more]

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