Estrogen Regulates Snail and Slug in the Down-Regulation of E-Cadherin and Induces Metastatic Potential of Ovarian Cancer Cells through Estrogen Receptor α

Abstract

Tumorigenesis is a multistep process involving dysregulated cell growth and metastasis. Considerable evidence implicates a mitogenic action of estrogen in early ovarian carcinogenesis. In contrast, its influence in the metastatic cascade of ovarian tumor cells remains obscure. In the present study, we showed that 17beta-estradiol (E2) increased the metastatic potential of human epithelial ovarian cancer cell lines. E2 treatment led to clear morphological changes characteristic of epithelial-mesenchymal transition (EMT) and an enhanced cell migratory propensity. These morphological and functional alterations were associated with changes in the abundance of EMT-related genes. Upon E2 stimulation, expression and promoter activity of the epithelial marker E-cadherin were strikingly suppressed, whereas EMT-associated transcription factors, Snail and Slug, were significantly up-regulated. This up-regulation was attributed to the increase in gene transcription activated by E2. Depletion of endogenous Snail or Slug using small interfering RNA (siRNA) attenuated E2-mediated decrease in E-cadherin. In addition, E2-induced cell migration was also neutralized by the siRNAs, suggesting that both transcription factors are indispensable for the prometastatic actions of E2. More importantly, by using selective estrogen receptor (ER) agonists, forced expression, and siRNA approaches, we identified that E2 triggered the metastatic behaviors exclusively through an ERalpha-dependent pathway. We also showed that ERbeta had an opposing action on ERalpha because the presence of ERbeta completely inhibited the EMT and down-regulation of E-cadherin induced by ERalpha. Collectively, this study provides a compelling argument that estrogen can potentiate tumor progression by EMT induction and highlights the crucial role of ERalpha in ovarian tumorigenesis.

Transcriptome profiling reveals novel gene expression signatures and regulating transcription factors of TGFβ‐induced epithelial‐to‐mesenchymal transition

“…For example, TWIST1, TWIST2, HDAC6, MUC1, ETS2, NFkB, Jun, SP1 , and AP1 were previously reported as enhancers of EMT, and were found activated in postEMT cells. Other TFs, such as ER, SPDEF , and HMGA1 , were previously reported as repressors of EMT, and were found repressed in this study 18, 19, 20. Interestingly, SMAD7 was previously reported as an EMT repressor; we found that SMAD7 gene expression was consistently elevated after EMT induction and positively correlated with postEMT 21.…”

Hypoxia, Snail and incomplete epithelial–mesenchymal transition in breast cancer

“…Silencing of either Snail or Slug caused reversion of the mesenchymal-like phenotype, and in addition treatment with the oestrogen antagonist ICI was shown to overcome the inhibitory effect of E 2 on E-cadherin transcription, suggesting a crucial role for oestrogen and its receptor in EMT-dependent tumour progression. Interestingly, in the same study it was also demonstrated that presence of ERb had an opposing effect on ERa, in the context of EMT regulation, inhibiting the ERa-induced EMT (Park et al, 2008). These findings may explain the mechanism by which ER status regulates invasion and metastasis in breast cancer.…”

“…Moreover, aetiological factors such as, for example, age at first full-term pregnancy, affects the importance of Snail as a susceptibility marker, and single-nucleotide polymorphism (SNP) of Snail has been shown to be of importance for the oestrogen-related risk factor in relation to breast cancer risk (Yu et al, 2006). In one study it was demonstrated that 17b-estradiol (E 2 ) treatment, in an ERa mediated manner, resulted in increased metastatic potential, morphological changes characteristic of EMT and increased transcriptional activity of the Snail and Slug genes, accompanied by decreased levels of E-cadherin in an ovarian cancer cell line (Park et al, 2008). Silencing of either Snail or Slug caused reversion of the mesenchymal-like phenotype, and in addition treatment with the oestrogen antagonist ICI was shown to overcome the inhibitory effect of E 2 on E-cadherin transcription, suggesting a crucial role for oestrogen and its receptor in EMT-dependent tumour progression.…”

Membrane-Initiated Estradiol Signaling of Epithelial-Mesenchymal Transition-Associated Mechanisms Through Regulation of Tight Junctions in Human Breast Cancer Cells

“…*P<0.05 vs. control. Representative images of at least three independent experiments are shown other studies [24]. We analyzed phenotypical changes around the wound area, including wound shape, MCF-7 cell morphology, intercellular separation, formation of pseudopodia, and cytoskeletal dynamics of F-actin (Fig.…”