Background:The role of the developmental transcription factor GRHL2 in breast carcinogenesis is ill defined. Results: Loss of GRHL2 expression induces an epithelial-to-mesenchymal transition and a reduction in cancer cell proliferation. GRHL2 and ZEB1 transcription factors form a negative feedback loop. Conclusion: GRHL2 exhibits dual roles in breast cancer. Significance: This study suggests the significance of GRHL2 in breast carcinogenesis.

The transcription factor grainyhead-like 2 (GRHL2) plays a crucial role in various developmental processes. Although GRHL2 recently has attracted considerable interest in that it could be identified as a novel suppressor of the epithelial-to-mesenchymal transition, evidence is emerging that GRHL2 also exhibits tumour-promoting activities. Aim of the present study therefore was to help defining the relevance of GRHL2 for human cancers by performing a comprehensive immunohistochemical analysis of GRHL2 expression in normal (n 5 608) and (n 5 3,143) tumour tissues using tissue microarrays. Consistent with its accepted role in epithelial morphogenesis, GRHL2 expression preferentially but not exclusively was observed in epithelial cells. Regenerative and proliferating epithelial cells with stem cell features showed a strong GRHL2 expression. Highly complex GRHL2 expression patterns indicative of both reduced and elevated GRHL2 expression in tumours, possibly reflecting potential tumour-suppressing as well as oncogenic functions of GRHL2 in distinct human tumours, were observed. A dysregulation of GRHL2 expression for the first time was found in tumours of non-epithelial origin (e.g., astrocytomas, melanomas). We also report GRHL2 copy number gains which, however, did not necessarily translate into increased GRHL2 expression levels in cancer cells. Results obtained by meta-analysis of gene expression microarray data in conjunction with functional assays demonstrating a direct regulation of HER3 expression further point to a potential therapeutic relevance of GRHL2 in ovarian cancer. Hopefully, the results presented in this study may pave the way for a better understanding of the yet largely unknown function of GRHL2 in the initiation, progression and also therapy of cancers.The epithelial-to-mesenchymal transition (EMT) is a morphogenetic programme that plays a crucial role in cancer progression and metastasis. 1 EMT is characterized by multiple biochemical changes enabling polarized epithelial cells to acquire a mesenchymal cell phenotype, which includes transformation of cell morphology, enhanced migratory and invasive capacity, anoikisresistance, elevated chemo-and radioresistance, and increased cell survival. The initiation and completion of EMT or of the reverse process, the mesenchymal-to-epithelial transition (MET), is signalled by a variety of intrinsic and extrinsic factors and ultimately leads to alterations in the expression or activation of a set of transcription factors which in concert orchestrate the highly complex EMT/MET-associated phenotypical changes. 2 The developmental transcription factor grainyhead-like 2 (GRHL2), one of the three known mammalian homologues of Drosophila grainyhead, recently was identified as a novel EMTsuppressor molecule in breast cancer. 3,4 Evidence is accumulating that GRHL2 represses EMT, at least in part, through transcriptional up-regulation of epithelial junctional complex proteins, including E-Cadherin and claudins 3 and 4, 5,6 as well as by suppression of the EMT tran...