ESE-1/ELF3 mRNA expression associates with poor survival outcomes in HER2+ breast cancer patients and is critical for tumorigenesis in HER2+ breast cancer cells

Kar, Adwitiya; Gutierrez‐Hartmann, Arthur

doi:10.18632/oncotarget.18710

Cited by 16 publications

(14 citation statements)

References 50 publications

(80 reference statements)

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“…For instance, overexpression of ELF3 in lung cancer, HER2+ breast cancer, and liver cancer can facilitate the progression of tumors. [11][12][13] However, a previous study showed that loss of ELF3 induces epithelial to mesenchymal transition in ovarian cancer, indicating that ELF3 acts as a tumor suppressor. 34 It has also been demonstrated that overexpression of ELF3 in the cholangiocarcinoma cell line can significantly inhibit its proliferation.…”

Section: Discussionmentioning

confidence: 98%

“…Then, the E74-like ETS transcription factor 3 (ELF3) gene was recognized as the target of miR-1224-5p based on integrated bioinformatic analysis and experimental verification. ELF3 plays an important oncogenic role in several tumors, such as lung cancer, 11 liver cancer, 12 and breast cancer, 13 via the PI3K/AKT, ERK and EMT signaling pathways. To further investigate the specific functions of ELF3 in pancreatic cancer, Kyoto encyclopedia of genes and genomes (KEGG) pathway, gene ontology (GO), and gene set enrichment analysis (GSEA) studies were performed based on the TCGA and STRING databases.…”

Section: Introductionmentioning

confidence: 99%

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<p>The miR-1224-5p/ELF3 Axis Regulates Malignant Behaviors of Pancreatic Cancer via PI3K/AKT/Notch Signaling Pathways</p>

Kong¹,

Liu²,

Zheng³

et al. 2020

OTT

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Purpose: Aberrant expression of microRNAs contributes to the progression of pancreatic cancer by targeting downstream genes. A novel regulatory axis, miR-1224-5p/ELF3, was identified by bioinformatic analysis and experimental verification. Studies of the underlying molecular mechanisms behind this axis lead to a better understanding of the development of pancreatic cancer. Materials and Methods: The differential expression of miR-1224-5p and ELF3 was verified based on Gene Expression Omnibus (GEO) datasets and clinical samples. The relationship between miR-1224-5p and ELF3 was demonstrated by luciferase assay and Western blot. The related signaling pathways of the miR-1224-5p/ELF3 axis in pancreatic cancer were investigated by gene set enrichment analysis (GSEA) and verified by Western blot. An analysis between ELF3 expression and immune infiltration was performed. Cellular and animal experiments were utilized to explore the effects of miR-1224-5p and ELF3 in pancreatic cancer. Results: Suppressed expression of miR-1224-5p in pancreatic tumor tissues and cancer cells was identified first. Furthermore, miR-1224-5p is correlated with clinicopathological features, and decreased expression of miR-1224-5p indicates poor prognosis. miR-1224-5p serves as a tumor suppressor and inhibits malignant behaviors of pancreatic cancer based on in vivo and in vitro assays. The putative target gene ELF3 was predicted by bioinformatic analysis and confirmed by dual-luciferase reporter assay. Overexpression of ELF3 can improve the malignant behaviors of pancreatic cancer and demonstrates poor prognosis and advanced clinical stage. The inhibitory role of miR-1224-5p in pancreatic cancer is manifested by its direct targeting of ELF3. A negative correlation between ELF3 expression and immune cell infiltration was identified, suggesting an immunosuppressive state resulting from ELF3 overexpression. The PI3K/AKT/Notch signaling pathways and epithelial-tomesenchymal transition (EMT) are important underlying mechanisms. Conclusion: The miR-1224-5p/ELF3 axis may serve as a new diagnostic, therapeutic, and prognostic biomarker in pancreatic cancer. The related PI3K/AKT/Notch/EMT signaling pathways greatly promote the elucidation of the progression of pancreatic cancer.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

<p>The miR-1224-5p/ELF3 Axis Regulates Malignant Behaviors of Pancreatic Cancer via PI3K/AKT/Notch Signaling Pathways</p>

Kong¹,

Liu²,

Zheng³

et al. 2020

OTT

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“…Conversely, ELF3 may have a pro-tumorigenic role in HER2 + tumours, where ELF3 is upregulated due to HER2-signaling driven activation of the ELF3 promoter [ 37 , 38 ]. HER2 + breast cancers with high ELF3 mRNA expression have a worse outcome, and ELF3 knockdown in HER2 + breast cancer cell lines attenuated tumour growth through inhibition of AKT signaling [ 39 ]. ELF3 knockdown also inhibited the growth in HER2 + trastuzumab-resistant breast cancer cell lines [ 40 ].…”

Section: Introductionmentioning

confidence: 99%

ELF3, ELF5, EHF and SPDEF Transcription Factors in Tissue Homeostasis and Cancer

2018

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The epithelium-specific ETS (ESE) transcription factors (ELF3, ELF5, EHF and SPDEF) are defined by their highly conserved ETS DNA binding domain and predominant epithelial-specific expression profile. ESE transcription factors maintain normal cell homeostasis and differentiation of a number of epithelial tissues, and their genetic alteration and deregulated expression has been linked to the progression of several epithelial cancers. Herein we review the normal function of the ESE transcription factors, the mechanisms by which they are dysregulated in cancers, and the current evidence for their role in cancer progression. Finally, we discuss potential therapeutic strategies for targeting or reactivating these factors as a novel means of cancer treatment.

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“…ESE-1 belongs to the ETS family of transcription factors and has been associated with cancer progression. 6,7 However, its observed effects are controversial 9,18,19,22,[24][25][26][27][28][29][30]32,40,41 ; whether ESE-1 is oncogenic or tumor suppressive has not been clearly determined in colon cancer or in any other type of cancer using an in vivo mouse model. Since inflammatory bowel disease (IBD)-related carcinogenesis is a very common pathological and clinical aspect of colon cancer, we adopted an AOM-induced and DSS-promoted colon cancer model using ESE-1 knockout mice, which may potentially be more susceptible to colonic inflammation and neoplasia.…”

Section: Discussionmentioning

confidence: 99%

“…16 The ESE-1 gene locus (1q32.1) is amplified in 50% of early human ductal carcinoma cases, and overexpressed in HER2/neu activated breast cancer cells. 9,17 ESE-1/ ELF3 mRNA expression is associated with poor survival outcomes in HER2 + breast cancer patients 18 and promotes epithelial-mesenchymal transition (EMT) in breast cancer cells. 19 These data suggest a tumor promoting role for ESE-1.…”

mentioning

confidence: 99%

Identification of epithelial‐specific ETS‐1 (ESE‐1) as a tumor suppressor and molecular target of green tea compound, EGCG

Lee

Lou

et al. 2019

Molecular Carcinogenesis

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Epithelial specific ETS‐1 (ESE‐1) belongs to the E26 transformation‐specific transcription factor superfamily and is of great interest as a potential target for managing several types of cancer. Despite its clinical significance, the documented effects of ESE‐1 on cancer development and progression are contradictory and its underlying biological mechanism of action remains elusive. The objectives of this study are to investigate whether ESE‐1 is a tumor suppressor and to identify dietary anti‐cancer compound to activate ESE‐1 expression in human colon cancer model. ESE‐1 knockout and xenograft mouse models were used to examine the effect of ESE‐1 in colon tumorigenesis. Stable human colon cancer cell lines were used for in vitro mechanistic studies. ESE‐1 knockout in mice increased azoxymethane (AOM)‐induced and dextran sulfate sodium (DSS)‐promoted formation of aberrant crypt foci (ACF). Conversely, overexpression of ESE‐1 suppressed tumorigenicity in a xenograft mouse study, and repressed anchorage‐independent growth and migration/invasion in human colon cancer cells. Full length ESE‐1 localized abundantly in the nucleus, and internal deletion of nuclear localization sequence 2 (NLS2) reduced nuclear ESE‐1. Three lysine residues (318KKK320) in the NLS2 determine its nuclear localization. We identified epigallocatechin‐3‐gallate (EGCG) that acts as a transcriptional activator of ESE‐1 in human colon cancer cells. These findings propose a novel and promising molecular target of dietary anti‐cancer compounds for prevention of colon cancer.

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ESE-1/ELF3 mRNA expression associates with poor survival outcomes in HER2+ breast cancer patients and is critical for tumorigenesis in HER2+ breast cancer cells

Cited by 16 publications

References 50 publications

<p>The miR-1224-5p/ELF3 Axis Regulates Malignant Behaviors of Pancreatic Cancer via PI3K/AKT/Notch Signaling Pathways</p>

<p>The miR-1224-5p/ELF3 Axis Regulates Malignant Behaviors of Pancreatic Cancer via PI3K/AKT/Notch Signaling Pathways</p>

ELF3, ELF5, EHF and SPDEF Transcription Factors in Tissue Homeostasis and Cancer

Identification of epithelial‐specific ETS‐1 (ESE‐1) as a tumor suppressor and molecular target of green tea compound, EGCG

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