GATA3 Inhibits Breast Cancer Metastasis through the Reversal of Epithelial-Mesenchymal Transition

Abstract

GATA3, a transcription factor that regulates T lymphocyte differentiation and maturation, is exclusively expressed in early stage well differentiated breast cancers but not in advanced invasive cancers. However, little is understood regarding its activity and the mechanisms underlying this differential expression in cancers. Here, we employed GATA3-positive, non-invasive (MCF-7) and GATA3-negative, invasive (MDA-MB-231) breast cancer cells to define its role in the transformation between these two distinct phenotypes. Ectopic expression of GATA3 in MDA-MB-231 cells led to a cuboidal-like epithelial phenotype and reduced cell invasive activity. These cells also increased E-cadherin expression but decreased levels of vimentin, N-cadherin, and MMP-9. Further, MDA-MB-231 cells expressing GATA3 grew smaller primary tumors without metastasis compared with larger metastatic tumors derived from control MDA-MB-231 cells in xenografted mice. GATA3 was found to induce E-cadherin expression through binding GATA-like motifs located in the E-cadherin promoter. Blockade of GATA3 using small interfering RNA gene knockdown in MCF-7 cells triggered fibroblastic transformation and cell invasion, resulting in distant metastasis. Studies of human breast cancer showed that GATA3 expression correlated with elevated E-cadherin levels, ER expression, and long disease-free survival. These data suggest that GATA3 drives invasive breast cancer cells to undergo the reversal of epithelial-mesenchymal transition, leading to the suppression of cancer metastasis.GATA3 (GATA-binding protein 3) is a family member of zinc finger transcription factors (GATA1-GATA6) that bind with high affinity to the consensus DNA sites (T/A-GATA-A/G) (1, 2). GATA1, GATA2, and GATA3 are primarily expressed by hematopoietic cells, whereas GATA4, GATA5, and GATA6 are detectable in the cardiovascular system and endodermus-derived tissues, such as lung, liver, intestine, and pancreas (3). Functional studies of GATA3 in the lineage specification of hematopoietic cells have revealed that GATA3 mediates thymocyte maturation and is abundantly expressed by mature T lymphocytes (4, 5). Recently, it also has been found that GATA3 plays an essential role in the morphogenesis of embryonic mammary tissue. In the adult mammary gland, GATA3 acts on ductal epithelium to maintain the differentiation of luminal epithelial cells (6 -8); thereof, GATA3 is recognized as a key regulator of mammary tissue development and mammary gland formation.Over the past decade, considerable attention has been focused on the differential expression profile of GATA3 in different subtypes of human breast cancers. For instance, studies with differential gene expression techniques, including serial analysis of gene expression (available on the NCI, National Institutes of Health, Web site) and gene microarray have shown that GATA3 is highly expressed in estrogen receptor (ER) 2 -positive, early stage well differentiated breast cancers other than ER-negative, invasive cancers that are associated with worse ...

Loss of GATA3 in bladder cancer promotes cell migration and invasion

“…Overexpression of GATA3 in a GATA3-deficient breast cancer line resulted in upregulation of an epithelial marker (i.e., E-cadherin) and downregulation of mesenchymal markers (i.e., vimentin, N-cadherin) as well as MMP-9. 22 We showed similar results in bladder cancer lines; silencing of GATA3 induced the activity of MMP-2 and MMP-9 as well as the expression of these MMPs, VEGF, and N-cadherin, and reduced the expression of another epithelial marker β-catenin. On the other hand, we failed to demonstrate the effects of GATA3 on bladder cancer cell proliferation and the expression of cell cycle/apoptosis-related molecules, while GATA3 was shown to correlate with increased proliferation of differentiated luminal cells or immature progenitor cells of the mammary gland and leukemia cells.…”

BRCA1 and GATA3 corepress FOXC1 to inhibit the pathogenesis of basal-like breast cancers

“…GATA3 has been shown to inhibit breast cancer metastasis through the reversal of epithelial-mesenchymal transition (Yan et al, 2010). GATA3 has also been reported to be coexpressed with another good prognosis indicator, FOXA1, in luminal A breast cancers and the expression of both proteins are known to predict for good prognosis (Ademuyiwa et al, 2010).…”

“…We also observed by immunofluorescence an increase in E-cadherin expression and a change in cell morphology following FOXC1 si to a more 'epithelial-like' phenotype (Figure 5c (ii)). Conversely, GATA3 is known to promote ordered epithelial differentiation and reverse the EMT phenotype in breast tissue (Yan et al, 2010). We performed GATA3si knockdown in luminal MCF7 cells (Figure 5d (i)) resulting in a concomitant increase in the EMT-associated marker fibronectin with immunohistochemistry showing mesenchymal-like shape changes, loss of E-cadherin and a dramatic increase in fibronectin staining compared with scrambled control (SCR)siRNA (Figure 5d (ii)).…”

Redox Control of the Senescence Regulator Interleukin-1α and the Secretory Phenotype

“…However, the levels of the mesenchymal marker N-cadherin were unaffected by exposure to senescent CM (Fig. 7B), which is likely explained by the fact that MDA-MB-231 cells display unusually high basal expression of this protein (29). We next monitored EMT markers in A549 lung carcinoma cells exposed to CM from early and late passage cells.…”