ZEB1 Collaborates with ELK3 to Repress E-Cadherin Expression in Triple-Negative Breast Cancer Cells

Cho, Hyeon-Ju; Park, Jihoon; Kim, Kwangsoo; Kim, Hyung-Keun; Lee, Eunbyeol; Hwang, Sohyun; Kim, Seong‐Jin; Park, Kyung-Soon

doi:10.1158/1541-7786.mcr-19-0380

Cited by 29 publications

(35 citation statements)

References 41 publications

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“…Unlike MDA-MB231 cells, TGFβ-treated MCF7 cells that display morphological changes of EMT do not show suppression of E-cadherin, a typical epithelial phenotype marker (14). Recently, we reported that ELK3 is highly expressed in TNBC-like MDA-MB231 cells, where it functions as a transcriptional repressor of E-cadherin by collaborating with ZEB1 (15). Therefore, we hypothesized that ELK3 is the missing link that explains the different molecular responses of MDA-MB231 and MCF7 cells when they are treated with TGFβ.…”

Section: Resultsmentioning

confidence: 96%

SMAD3 promotes ELK3 expression following transforming growth factor β‑mediated stimulation of MDA‑MB231 cells

Park

2020

Oncol Lett

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Transforming growth factor-β (TGFβ) is a secreted cytokine whose aberrant spatiotemporal expression is related to cancer progression and metastasis. While TGFβ acts as a tumor suppressor in normal and premalignant stages, TGFβ functions as a tumor promoter during the malignant phases of tumor progression by prompting cancer cells to undergo epithelial-mesenchymal transition (EMT), which enhances tumor cell invasion and ultimately promotes metastasis to other organs. Extensive studies have been performed to uncover the molecular and cellular mechanisms underlying TGFβ inducing EMT in cancer cells. Here, we suggested that ELK3, which encodes a protein that orchestrates invasion and metastasis of triple negative breast cancer cells, is a downstream target of TGFβ-SMAD3 in MDA-MB231 cells. ELK3 expression was increased in a time-dependent manner upon TGFβ treatment. Chemical and molecular inhibition of the TGFβ receptor blocked the ability of TGFβ to induce ELK3 expression. Small interfering RNA-mediated suppression analysis revealed that SMAD3 induces TGFβ signaling to express ELK3. Moreover, the results of the luciferase reporter assay and chromatin immunoprecipitation analysis showed that SMAD3 directly binds to the SMAD-binding element on the promoter of ELK3 to activate gene expression following TGFβ stimulation. We concluded that ELK3 is a novel downstream target of TGFβ-SMAD3 signaling in aggressive breast cancer cells.

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Section: Resultsmentioning

confidence: 96%

SMAD3 promotes ELK3 expression following transforming growth factor β‑mediated stimulation of MDA‑MB231 cells

Park

2020

Oncol Lett

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“…On the other hand, ZEB1 downregulation mediated by PKCα leads to inhibition of mesenchymal phenotype, cell migration, and invasiveness [ 107 ]. ZEB1 is known to cooperate with ELK3, a ternary complex factor from the ETS TFs family, to repress E-cadherin by transcriptional activation of ELK3 expression [ 108 ]. Suppression of ELK3 through epigenetic activation of GATA3 rendered cancer cells unresponsive to TGF-β and led to their reprogramming into a non-invasive, cuboidal-like, epithelial state, as observed both in vitro and in vivo [ 109 ].…”

Section: Mechanisms Regulating Epithelial–mesenchymal Plasticitymentioning

confidence: 99%

Phenotypic Heterogeneity of Triple-Negative Breast Cancer Mediated by Epithelial–Mesenchymal Plasticity

Kvokačková

Remšík

Jolly

et al. 2021

Cancers

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Triple-negative breast cancer (TNBC) is a subtype of breast carcinoma known for its unusually aggressive behavior and poor clinical outcome. Besides the lack of molecular targets for therapy and profound intratumoral heterogeneity, the relatively quick overt metastatic spread remains a major obstacle in effective clinical management. The metastatic colonization of distant sites by primary tumor cells is affected by the microenvironment, epigenetic state of particular subclones, and numerous other factors. One of the most prominent processes contributing to the intratumoral heterogeneity is an epithelial–mesenchymal transition (EMT), an evolutionarily conserved developmental program frequently hijacked by tumor cells, strengthening their motile and invasive features. In response to various intrinsic and extrinsic stimuli, malignant cells can revert the EMT state through the mesenchymal–epithelial transition (MET), a process that is believed to be critical for the establishment of macrometastasis at secondary sites. Notably, cancer cells rarely undergo complete EMT and rather exist in a continuum of E/M intermediate states, preserving high levels of plasticity, as demonstrated in primary tumors and, ultimately, in circulating tumor cells, representing a simplified element of the metastatic cascade. In this review, we focus on cellular drivers underlying EMT/MET phenotypic plasticity and its detrimental consequences in the context of TNBC cancer.

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“…Studying the effect of BCL11A zinc protein family members on repressing E-cadherin levels like zinc finger Ebox-binding (ZEB) proteins will be investigated in this study. E-cadherin is a membrane adhesion protein that plays a crucial role in cancer progression and may be repressed by some zinc finger protein family members that encode cysteine two and histidine two (C2H2) gene [24]. E-cadherin is responsible for cell-to-cell adhesion between epithelial cells, resulting in cell layering as well as regulating cell morphogenesis, repression of E-cadherin, and restraining its functions cause the cell-to-cell adhesion and cell integrity to fade gradually [25].…”

Section: Zincmentioning

confidence: 99%

Clinical Significance of the Transcription Factor SOX11, Cell-Cell Adhesion Protein E-cadherin and Zinc Finger Protein BCL11A in the Diagnosis of Breast Cancer

Salama

Hamdy

Elshimy

et al. 2021

Archives of Pharmaceutical Sciences Ain Shams University

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Transcription factors (TFs) as SRY-Box transcription factor 11 (SOX11) and B-cell lymphoma/leukemia 11A (BCL11A) role in breast cancer (BC) as well as their effect on epithelial cadherin (E-cadherin) membrane protein which is a metastasis suppressor is a question that must be addressed. Among the thirty-nine BC, patients were invasive ductal carcinoma (IDC), twenty females with benign fibroadenomas and/or fibrocystic changes, and nineteen healthy control. We quantified SOX11, E-cadherin, and BCL11A serum levels in Egyptian women with BC and determined their cut-off values. The correlation between SOX11, E-cadherin, and BCL11A sera levels and cancer antigen (CA15.3), as well as carcinoembryonic antigen (CEA), were assessed and quantified by ELISA. Finally, we explored the association between SOX11, E-cadherin levels, and BCL11A as potential markers according to histo-and clinicopathological characteristics and hormone receptors. Significant increase in E-cadherin serum levels in the cancerous than the non-cancerous group (P0.05). A significant decrease in SOX11 and BCL11A serum levels (P<0.05) was detected in the non-cancerous group than the cancerous group. In addition, a decrease in SOX11 levels was observed in the later stage of BC cases, while earlier stage BC cases were associated with an increase in SOX11. In addition to the significant positive correlation (P<0.05) between SOX11 and BCL11A proteins in blood suggesting a common inter-regulatory pathway. SOX11 has an excellent area under the curve (AUC) either solely or combined with CA15.3. Earlier stages in BC were associated with an increase in SOX11 serum levels (P<0.05).

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ZEB1 Collaborates with ELK3 to Repress E-Cadherin Expression in Triple-Negative Breast Cancer Cells

Cited by 29 publications

References 41 publications

SMAD3 promotes ELK3 expression following transforming growth factor β‑mediated stimulation of MDA‑MB231 cells

SMAD3 promotes ELK3 expression following transforming growth factor β‑mediated stimulation of MDA‑MB231 cells

Phenotypic Heterogeneity of Triple-Negative Breast Cancer Mediated by Epithelial–Mesenchymal Plasticity

Clinical Significance of the Transcription Factor SOX11, Cell-Cell Adhesion Protein E-cadherin and Zinc Finger Protein BCL11A in the Diagnosis of Breast Cancer

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