Over-expression of ERT(ESX/ESE-1/ELF3), an ets-related transcription factor, induces endogenous TGF-β type II receptor expression and restores the TGF-β signaling pathway in Hs578t human breast cancer cells

Abstract

The epithelium-speci®c transcription factor, ERT/ESX/ ESE-1/ELF3, binds to the TGF-b RII promoter in a sequence speci®c manner and regulates its expression. In this study, we investigated whether ERT could regulate endogenous TGF-b RII expression in Hs578t breast cancer cells. Analyses of the Hs578t parental cell line revealed low RII mRNA expression and resistance to the growth inhibitory eects of TGF-b. Infection of this cell line with a retroviral construct expressing ERT induced higher levels of endogenous RII mRNA expression and protein expression relative to cells infected with chloramphenicol acetyltransferase (CATneo) as a control. Relative to control cells, the ERTneo-expressing Hs578t cells show approximately a 50% reduction in cell growth in the presence of exogenous TGF-b1, as well as a fourfold higher induction of activation in transient transfection assays using the 3TP-luciferase reporter construct. When transplanted into athymic mice, ERTexpressing Hs578t cells showed decreased and delayed tumorigenicity compared with control cells. This data strongly suggests that ERT plays an important role as a transcriptional activator of TGF-b RII expression, and that deregulated ERT expression may play a critical role in rendering Hs578t human breast cancer cells insensitive to TGF-b's growth inhibitory eects. Oncogene (2000) 19, 151 ± 154.

Elf3 plays a role in regulating bronchiolar epithelial repair kinetics following Clara cell-specific injury

“…The best known candidate is the gene encoding for TGF-b RII, as several studies have clearly shown that Elf3 can bind to the promoter and regulate transcription of the TGF-b RII gene. [27][28][29][37][38][39] Moreover, it has also been reported that Elf3À/À mice express reduced protein levels of TGF-b RII in the developing small intestinal epithelium when compared with Elf3 þ / þ mice. 26 Although TGF-b RII is a potent inhibitor of cell proliferation, it is very important for the induction of epithelial cell differentiation.…”

“…However, Elf3 has been shown to be involved in regulating the expression of genes involved in controlling epithelial cell proliferation and differentiation during embryonic/fetal development and oncogenesis. 17,26,30,37,38,[42][43][44] Therefore, the delayed kinetics of cell proliferation/mitosis and Clara cell reconstitution observed within the bronchiolar airway epithelium of Elf3À/À mice is more likely because of changes in gene expression for proteins involved in regulating epithelial cell proliferation and/or differentiation during repair after naphthalene-induced Clara cell ablation. The best known candidate is the gene encoding for TGF-b RII, as several studies have clearly shown that Elf3 can bind to the promoter and regulate transcription of the TGF-b RII gene.…”

Multiple roles of the epithelium-specific ETS transcription factor, ESE-1, in development and disease

“…50 In contrast, overexpression of ESE-1 in human breast cancer cells has been shown to induce endogenous TGF-b RII expression, resulting in restitution of the TGF-b signaling pathway along with a significant reduction in resistance to the growth inhibitory effects of TGF-b. 32 …”

“…34 In human colonic epithelial cells, ESE-1 has also been shown to regulate gene expression of the proinflammatory cytokine, macrophage inflammatory protein-3a (MIP-3a). 39 Another group has previously reported that CR6-interacting factor 1 (Crif1) plays an essential role in Elf3-mediated intestinal development by functioning as a transcriptional co-activator of Elf3 during terminal differentiation of the 25,30 Mouse bronchiolar airway epithelium 42 Mouse embryonal carcinoma cell line (F9) 33,35,37 Human embryonic kidney cell line (HEK 293T) 33,35,37 Human hepatoblastoma cell line (HepG2) 31 Human gastric cancer cell line (SNU-620) 31 Human colon cancer cell line (RKO) 34 Human breast cancer cell lines (SK-BR3, Hs578t) 31,32 Human cervical cancer cell line (HeLa 229) 31,33 Macrophage inflammatory protein-3a (MIP-3a)m Human colonic epithelial cell line (Caco-2) 39 Small proline-rich protein 1B (SPRR1B)m Primary human tracheobronchial epithelial cells 41 Human bronchial epithelial cell line (BEAS-2B) 41 Human lung adenocarcinoma epithelial cell line (NCI-H441) 41 Epithelium-specific ETS transcription factor-3 (ESE-3)m Human bronchial epithelial cell line (BEAS-2B) 44 Human lung carcinoma cell line (A549) 44 Interleukin-6 (IL-6)m Mouse lung tissue 44 Primary mouse airway epithelial cells 47 Primary mouse bone marrow-derived dendritic cells 47 Human bronchial epithelial cell line (BEAS-2B) 47 Interleukin-12 (IL-12)m Primary mouse bone marrow-derived dendritic cells 47 Lysozyme (LYZ)m Primary human bronchial airway epithelial cells 46 Human lung carcinoma cell line (A549) 46 Human lung mucoepidermoid carcinoma-derived cell line (NCI-H292) 46 Human lung adenocarcinoma epithelial cell line (NCI-H441) …”

“…30 Indeed, many in vitro studies have also established that the TGF-b RII gene is a definite target of Elf3, and that Elf3 transactivates the TGF-b RII gene promoter by binding to two adjacent ETS binding sites. [31][32][33][34][35][36][37] Interestingly, human gastric cancer cell lines do not express ESE-1 mRNA and in turn show undetectable levels of TGF-b RII mRNA. 38 Further evidence of ESE-1-mediating TGF-b RII gene expression has also been provided from experiments with human colon cancer cell lines.…”