Dataset Information

The TGFβ2-Snail1-miRNA_TGFβ2 Circuitry is Critical for the Development of Aggressive Functions in Breast Cancer.

ABSTRACT: There have been contradictory reports on the biological role of transforming growth factor-βs (TGFβs) in breast cancer (BC), especially with regard to their ability to promote epithelial-mesenchymal transition (EMT). Here, we show that TGFβ2 is preferentially expressed in mesenchymal-like BCs and maintains the EMT phenotype, correlating with cancer stem cell-like characteristics, growth, metastasis and chemo-resistance and predicting worse clinical outcomes. However, this is only true in ERα^- BC. In ERα⁺ luminal-type BC, estrogen receptor interacts with p-Smads to block TGFβ signalling. Furthermore, we also identify a microRNAs (miRNAs) signature (miRNAs_TGFβ2 ) that is weakened in TGFβ2-overexpressing BC cells. We discover that TGFβ2-Snail1 recruits enhancer of zeste homolog-2 to convert miRNAsTGFβ2 promoters from an active to repressive chromatin configuration and then repress miRNAs_TGFβ2 transcription, forming a negative feedback loop. On the other hand, miRNAs_TGFβ2 overexpression reverses the mesenchymal-like traits in agreement with the inhibition of TGFβ2-Snail1 signalling in BC cells. These findings clarify the roles of TGFβ2 in BC and suggest novel therapeutic strategies based on the TGFβ2-Snail1-miRNAs_TGFβ2 loop for a subset type of human BCs.

SUBMITTER: Luo L

PROVIDER: S-EPMC10831563 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The TGFβ2-Snail1-miRNA<sub>TGFβ2</sub> Circuitry is Critical for the Development of Aggressive Functions in Breast Cancer.

Luo Liyun L Xu Ning N Fan Weina W Wu Yixuan Y Chen Pingping P Li Zhihui Z He Zhimin Z Liu Hao H Lin Ying Y Zheng Guopei G

Clinical and translational medicine 20240201 2

There have been contradictory reports on the biological role of transforming growth factor-βs (TGFβs) in breast cancer (BC), especially with regard to their ability to promote epithelial-mesenchymal transition (EMT). Here, we show that TGFβ2 is preferentially expressed in mesenchymal-like BCs and maintains the EMT phenotype, correlating with cancer stem cell-like characteristics, growth, metastasis and chemo-resistance and predicting worse clinical outcomes. However, this is only true in ERα<sup ...[more]

PMID: 38299307

Similar Datasets

Project description:In aggressively growing tumors, hypoxia induces HIF-1α expression promoting angiogenesis. Previously, we have shown that overexpression of oncogenic microRNAs (miRNAs, miRs) miR526b/miR655 in poorly metastatic breast cancer cell lines promotes aggressive cancer phenotypes in vitro and in vivo. Additionally, miR526b/miR655 expression is significantly higher in human breast tumors, and high miR526b/miR655 expression is associated with poor prognosis. However, the roles of miR526b/miR655 in hypoxia are unknown. To test the relationship between miR526b/miR655 and hypoxia, we used various in vitro, in silico, and in situ assays. In normoxia, miRNA-high aggressive breast cancer cell lines show higher HIF-1α expression than miRNA-low poorly metastatic breast cancer cell lines. To test direct involvement of miR526b/miR655 in hypoxia, we analyzed miRNA-high cell lines (MCF7-miR526b, MCF7-miR655, MCF7-COX2, and SKBR3-miR526b) compared to controls (MCF7 and SKBR3). CoCl2-induced hypoxia in breast cancer further promotes HIF-1α mRNA and protein expression while reducing VHL expression (a negative HIF-1α regulator), especially in miRNA-high cell lines. Hypoxia enhances oxidative stress, epithelial to mesenchymal transition, cell migration, and vascular mimicry more prominently in MCF7-miR526b/MCF7-miR655 cell lines compared to MCF7 cells. Hypoxia promotes inflammatory and angiogenesis marker (COX-2, EP4, NFκB1, VEGFA) expression in all miRNA-high cells. Hypoxia upregulates miR526b/miR655 expression in MCF7 cells, thus observed enhancement of hypoxia-induced functions in MCF7 could be attributed to miR526b/miR655 upregulation. In silico bioinformatics analysis shows miR526b/miR655 regulate PTEN (a negative regulator of HIF-1α) and NFκB1 (positive regulator of COX-2 and EP4) expression by downregulation of transcription factors NR2C2, SALL4, and ZNF207. Hypoxia-enhanced functions in miRNA-high cells are inhibited by COX-2 inhibitor (Celecoxib), EP4 antagonist (ONO-AE3-208), and irreversible PI3K/Akt inhibitor (Wortmannin). This establishes that hypoxia enhances miRNA functions following the COX-2/EP4/PI3K/Akt pathways and this pathway can serve as a therapeutic target to abrogate hypoxia and miRNA induced functions in breast cancer. In situ, HIF-1α expression is significantly higher in human breast tumors (n = 96) compared to non-cancerous control tissues (n = 20) and is positively correlated with miR526b/miR655 expression. In stratified tumor samples, HIF-1α expression was significantly higher in ER-positive, PR-positive, and HER2-negative breast tumors. Data extracted from the TCGA database also show a strong correlation between HIF-1α and miRNA-cluster expression in breast tumors. This study, for the first time, establishes the dynamic roles of miR526b/miR655 in hypoxia.

Dataset Information

The TGFβ2-Snail1-miRNA_TGFβ2 Circuitry is Critical for the Development of Aggressive Functions in Breast Cancer.

Publications

The TGFβ2-Snail1-miRNA<sub>TGFβ2</sub> Circuitry is Critical for the Development of Aggressive Functions in Breast Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

The TGFβ2-Snail1-miRNATGFβ2 Circuitry is Critical for the Development of Aggressive Functions in Breast Cancer.

Publications

The TGFβ2-Snail1-miRNA<sub>TGFβ2</sub> Circuitry is Critical for the Development of Aggressive Functions in Breast Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

The TGFβ2-Snail1-miRNA_TGFβ2 Circuitry is Critical for the Development of Aggressive Functions in Breast Cancer.