Abnormalities in miRNAome contribute to aberrant expression of immune checkpoint ligands on breast cancer cells: An epigenetic mechanism of tumor immune privilege

The small GTPase RHOJ is a key regulator of breast cancer metastasis by promoting cell migration and invasion. The prometastatic stimulus TGF-β activates RHOJ transcription via megakaryocytic leukemia 1 (MKL1). The underlying epigenetic mechanism is not clear. Here, we report that MKL1 deficiency led to disrupted assembly of the RNA polymerase II preinitiation complex on the RHOJ promoter in breast cancer cells. This could be partially explained by histone H3K9/H3K27 methylation status. Further analysis confirmed that the H3K9/H3K27 dual demethylase JHDM1D/KDM7A was essential for TGF-β-induced RHOJ transcription in breast cancer cells. MKL1 interacted with and recruited KDM7A to the RHOJ promoter to cooperatively activate RHOJ transcription. KDM7A knockdown attenuated migration and invasion of breast cancer cells in vitro and mitigated the growth and metastasis of breast cancer cells in nude mice. KDM7A expression level, either singularly or in combination with that of RHOJ, could be used to predict prognosis in breast cancer patients. Of interest, KDM7A appeared to be a direct transcriptional target of TGF-β signaling. A SMAD2/SMAD4 complex bound to the KDM7A promoter and mediated TGF-β-induced KDM7A transcription. In conclusion, our data unveil a novel epigenetic mechanism whereby TGF-β regulates the transcription of the prometastatic small GTPase RHOJ. Screening for small-molecule inhibitors of KDM7A may yield effective therapeutic solutions to treat malignant breast cancers.

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MiR-539 inhibits the malignant behavior of breast cancer cells by targeting SP1

Biochemistry and Cell Biology ◽

10.1139/bcb-2019-0111 ◽

2020 ◽

Vol 98 (3) ◽

pp. 426-433 ◽

Cited By ~ 3

Author(s):

Fenglin Cai ◽

Luhong Chen ◽

Yuting Sun ◽

Chunlan He ◽

Deyuan Fu ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Inhibitory Effect ◽

Aberrant Expression ◽

Mesenchymal Transition ◽

Promising Target ◽

Specificity Protein ◽

Cancer Tissues

The aberrant expression of microRNAs (miRNAs) is involved in the initiation and progression of human cancers. In our study, we found that miR-539 was down-regulated in breast cancer tissues and cell lines. Decreased expression of miR-539 was significantly associated with lymph node metastasis in patients with breast cancer. Overexpression of miR-539 inhibited the proliferation and promoted apoptosis of breast cancer cells. Moreover, highly expressed miR-539 significantly suppressed the epithelial–mesenchymal transition (EMT) and sensitized cells to cisplatin treatment. Mechanistically, miR-539 was found to target the specificity protein 1 (SP1) and down-regulated the expression of SP1 in breast cancer cells. Knockdown of miR-539 consistently increased the expression of SP1. The expression of miR-539 in breast cancer tissues was negatively correlated with the expression of SP1. Restoration of SP1 significantly attenuated the inhibitory effect of miR-539 on the proliferation of breast cancer cells. Taken together, our results indicate that miR-539 has a tumor suppressive role in breast cancer via targeting SP1, suggesting miR-539 as a promising target for the diagnosis of breast cancer.

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ZNF217 confers resistance to the pro-apoptotic signals of paclitaxel and aberrant expression of Aurora-A in breast cancer cells

Molecular Cancer ◽

10.1186/1476-4598-9-291 ◽

2010 ◽

Vol 9 (1) ◽

pp. 291 ◽

Cited By ~ 26

Author(s):

Aurélie Thollet ◽

Julie A Vendrell ◽

Léa Payen ◽

Sandra E Ghayad ◽

Sabrina Ben Larbi ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Aurora A ◽

Aberrant Expression

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LncRNA DANCR contributes to tumor progression via targetting miR-216a-5p in breast cancer: lncRNA DANCR contributes to tumor progression

Bioscience Reports ◽

10.1042/bsr20181618 ◽

2019 ◽

Vol 39 (4) ◽

Cited By ~ 12

Author(s):

Weiyang Tao ◽

Chunyang Wang ◽

Bifa Zhu ◽

Guoqiang Zhang ◽

Da Pang

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Tumor Progression ◽

Cancer Cells ◽

Cell Line ◽

Breast Cancer Cells ◽

Biological Effects ◽

Tumor Promoter ◽

Aberrant Expression ◽

Proliferation And Invasion

Abstract Breast cancer, the most frequently occurring malignant tumor, has high mortality rate, especially triple-negative breast cancer (TNBC). LncRNA-differentiation antagonizing non-protein coding RNA (lncRNA DANCR) has been found that its aberrant expression was associated with tumor progression and it was promising to be a potential target for cancer therapy. The goal of the present study was to explore the biological effects and underlying mechanism of DANCR in breast cancer. Our results showed that DANCR was up-regulated in TNBC tissues and breast cancer cells compared with normal breast tissues and cells, and higher DANCR level suggested poorer prognosis, implying that it was promising to be a novel biomarker used for TNBC diagnosis and prognosis. To better research the functions and mechanism of DANCR on breast cancer cells, we selected two cell lines used for next study: one TNBC cell line–MDA-MB-231 and one ER-positive breast cancer cell line–MCF-7. Further study indicated that DANCR overexpression significantly promoted cell proliferation and invasion in vitro and contributed to tumor growth in vivo. To deeply understand its molecular mechanism, miRNA-216a-5p was identified as a target of DANCR by bioinformatic analysis. Experiments demonstrated that miRNA-216a-5p interacted with DANCR and its inhibitor could weaken the influences induced by DANCR knockdown for cancer cells, including cell proliferation and invasion, and the expression of Nanog, SOX2, and OCT4. Therefore, DANCR might act as a tumor promoter by targetting miRNA-216a-5p, which might provide a potential therapy target for breast cancer treatment.

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Molecular mechanisms for aberrant expression of the human breast cancer specific gene 1 in breast cancer cells: control of transcription by DNA methylation and intronic sequences

Oncogene ◽

10.1038/sj.onc.1204668 ◽

2001 ◽

Vol 20 (37) ◽

pp. 5173-5185 ◽

Cited By ~ 35

Author(s):

AiPing Lu ◽

Anu Gupta ◽

Cong Li ◽

Thomas E Ahlborn ◽

YongSheng Ma ◽

...

Keyword(s):

Breast Cancer ◽

Dna Methylation ◽

Cancer Cells ◽

Human Breast Cancer ◽

Breast Cancer Cells ◽

Molecular Mechanisms ◽

Specific Gene ◽

Human Breast ◽

Aberrant Expression

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Sodium Channel Nav1.5 Controls Epithelial-to-Mesenchymal Transition and Invasiveness in Breast Cancer Cells Through its Regulation by the Salt-Inducible Kinase-1

Scientific Reports ◽

10.1038/s41598-019-55197-5 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 4

Author(s):

Frédéric Gradek ◽

Osbaldo Lopez-Charcas ◽

Stéphanie Chadet ◽

Lucile Poisson ◽

Lobna Ouldamer ◽

...

Keyword(s):

Breast Cancer ◽

Transcription Factor ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Epithelial To Mesenchymal Transition ◽

Aberrant Expression ◽

Mesenchymal Transition ◽

Voltage Gated Sodium Channels ◽

Cell Invasiveness ◽

Mcf 7

AbstractLoss of epithelial polarity and gain in invasiveness by carcinoma cells are critical events in the aggressive progression of cancers and depend on phenotypic transition programs such as the epithelial-to-mesenchymal transition (EMT). Many studies have reported the aberrant expression of voltage-gated sodium channels (NaV) in carcinomas and specifically the NaV1.5 isoform, encoded by the SCN5A gene, in breast cancer. NaV1.5 activity, through an entry of sodium ions, in breast cancer cells is associated with increased invasiveness, but its participation to the EMT has to be clarified. In this study, we show that reducing the expression of NaV1.5 in highly aggressive human MDA-MB-231 breast cancer cells reverted the mesenchymal phenotype, reduced cancer cell invasiveness and the expression of the EMT-promoting transcription factor SNAI1. The heterologous expression of NaV1.5 in weakly invasive MCF-7 breast cancer cells induced their expression of both SNAI1 and ZEB1 and increased their invasive capacities. In MCF-7 cells the stimulation with the EMT-activator signal TGF-β1 increased the expression of SCN5A. Moreover, the reduction of the salt-inducible kinase 1 (SIK1) expression promoted NaV1.5-dependent invasiveness and expression of EMT-associated transcription factor SNAI1. Altogether, these results indicated a prominent role of SIK1 in regulating NaV1.5-dependent EMT and invasiveness.

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The roles of microRNA-328-3p on proliferation and radiotherapy in breast cancer

10.21203/rs.3.rs-742188/v1 ◽

2021 ◽

Author(s):

Ying Shi ◽

Pengli Jiang ◽

Jinqiu Li ◽

Shengnan Xu ◽

Bin Liu

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Breast Carcinogenesis ◽

Aberrant Expression ◽

Induced Apoptosis ◽

Cancer Tissues ◽

The Impact

Abstract Objectives MicroRNAs regulates varieties of molecular pathways and involve in breast carcinogenesis. Here both breast cancer cell lines and human breast cancer tissues were used to investigate the roles of miR-328-3p in breast cancer. Methods The impact of miR-328-3p on proliferation of MDA-MB-231 and T47D cells was determined by MTT assay. transwell migration and matrigel invasion assays were performed to evaluate effects of miR-328-3p on migration and invasion of breast cancer cells. Caspase 3/7 activities were measured to examine the impact of miR-328-3p on radiotherapy-induced apoptosis in breast cancer cells. The possible binding site of miR-328-3p was verified by dual-luciferase reporter assay. Quantitative real-time polymerase chain reaction was performed to detect miR-328-3p expression level in breast cancer tissues. Western blot and immunohistochemical studies were used to examine protein expression in breast cancer cells and breast cancer tissue, respectively. Results miR-328-3p involved growth, migration and invasion in breast cancer cells and was associated with radiotherapy sensitivity. MiR-328-3p enhanced radiation-induced apoptosis in breast cancer cells by regulating BAX and Bcl-2 expression. Meanwhile, aberrant expression of miR-328-3p was associated with altered expression of PTEN and p-AKT in breast cancer cells. Further study showed miR-328-3p bound to 3’-UTR of PTEN. In addition, breast cancer tissues showed higher level of miR-328-3p than normal breast tissue and higher level of miR-328-3p was seen in lower stage in breast cancer. Conclusions miR-328-3p displayed essential functions in breast carcinogenesis and might be used to predict radiotherapy response and prognosis in breast cancer.

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