MicroRNA expression data from an epithelial-mesenchymal transition (EMT) model of triple negative breast cancer (TNBC).
Ontology highlight
ABSTRACT: Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer due to lack of effective targeted therapies. Here, we report that the expression of miR-4417 is suppressed during the progression of TNBC cells from non-malignant to the malignant stage. miR-4417 is localized to chromosome 1p36, a region with high loss of heterozygosity in multiple cancers, and its biogenesis is DICER-dependent. Low expression of miR-4417 is significantly associated with worse prognosis in TNBC patients, while overexpression of miR-4417 is sufficient to inhibit migration and tumorigenecity of TNBC cells in vitro. Overall, our findings suggest that miR-4417 exerts a tumor suppressive effect and thereby could serve as a prognostic biomarker and therapeutic tool against TNBC. We used microarrays to profile the global miRNA changes during EMT to identify putative tumor suppressors and prognostic biomarkers for TNBC.
Project description:The expression levels of JMJD6 and its correlation with H2A.XY39ph differed in TNBC and non-TNBC cells. In addition, we have previously shown that H2A.XY39ph levels are positively correlated with tumor size, histological grade and advanced TNM stage in breast cancer. To analyze the role of JMJD6 in regulating the characteristics of different subtypes of breast cancer, the transcriptomes of TNBC cells (SUM159) and non-TNBC cells (HCC1569) that overexpressed JMJD6 were compared. We speculate that JMJD6 overexpression cause autophagy pathway activation in TNBC via enhancing ATG genes expression.
Project description:Triple-negative breast cancer (TNBC) has a greater invasive and metastatic potential than non-TNBC, leading to a poorer prognosis because of the absence of viable therapeutic targets. Tumor necrosis factor-alpha (TNF-α), which is aberrantly activated in TNBC, plays a pivotal role in TNBC metastasis and progression. The ability of TNF-α to promote TNBC progression is unique when compared with its ability to promote non-TNBC progression; however, the underlying mechanism remains unclear. TNF-α specifically enhanced the invasive and metastatic potential of TNBC compared with that of non-TNBC. Analysis of the differentially expressed miRNAs showed that TNF-α upregulated miR-5001-5p expression in TNBC cells. The results of transcriptomic sequencing combined with subsequent verification analysis indicated that MNK2a was significantly downregulated following miR-5001-5p overexpression. Evidence from dual-luciferase reporter assays confirmed that miR-5001-5p bound to the MNK2a 3' UTR region and inhibited the activation of the p38 MAPK pathway. Our results provide novel insights into the molecular mechanism by which TNF-α promotes epithelial–mesenchymal transition in TNBC through the TNF-α–miR-5001-5p–MNK2a–p38 MAPK signaling axis, eventually enhancing the invasive and metastatic potential of TNBC. We discovered a novel mechanism of invasion and metastasis in TNBC whereby TNF-α upregulated the expression of miR-5001-5p, which downregulated MNK2a by binding to its 3' UTR region. This inhibited the activation of the p38 MAPK pathway, following which MNK2a promoted epithelial–mesenchymal transition in TNBC. This mechanism offers a theoretical basis for TNBC-targeted therapy and also serves as a novel therapeutic target.
Project description:The pattern recognition receptor long pentraxin-3 (PTX3) plays conflicting roles in cancer by acting as an oncosuppressor or as a pro-tumor mediator depending on tumor context. Triple negative breast cancer (TNBC) represents the most aggressive histotype of breast cancer, characterized by the lack of efficacious therapeutic targets/approaches and poor prognosis. In this study, in silico data and experimental evidences indicate that PTX3 is produced by tumor parenchyma in TNBC and that its expression levels correlate with tumor stage. On this basis, the impact of PTX3 silencing or its overexpression on the tumorigenic potential of TNBC cell lines was analyzed. Gene expression and in vitro results demonstrate that high levels of PTX3 expression confer a high aggressive/proliferative phenotype, fosters stem-like features, and rewires the energy metabolism in TNBC cells. This results in a more tumorigenic potential in vivo when TNBC cells are grafted in immune-compromised and syngeneic animals. Mechanistically, our data reveal a strong positive correlation between PTX3 expression and the antitumor activity of Toll-like receptor 4 (TLR4) inhibition in TBNC, demonstrating for the first time that PTX3-driven TNBC aggressiveness is due to PTX3-mediated activation of TLR4 signaling. Altogether, these data shed light on the role of tumor-produced PTX3 in TNBC and uncover the importance of the PTX3/TLR4 pathway for therapeutic and prognostic exploitation in TNBC.
Project description:To define transcriptional dependencies of TNBCs, we identified transcription factors highly and specifically expressed in primary TNBCs and tested their requirement for cell growth in a panel of breast cancer cell lines. We found that EN1 is overexpressed in TNBCs and its downregulation preferentially and significantly reduces cellular viability and tumorigenicity in TNBC cell lines. Based on RNA-seq and ChIPseq we found that EN1 regulates genes involved in angiogenesis, neurogenesis, and axon guidance in breast cancer cells. Higher expression of EN1 correlates with shorter overall survival among TNBC patients and with higher risk of developing brain metastases. Thus, EN1 is a prognostic marker and a therapeutic target in this particularly lethal subset of TNBCs.
Project description:Efforts to improve the clinical outcome of highly aggressive triplenegative breast cancer (TNBC) have been hindered by the lack of effective targeted therapies. Hence, it is important to identify the specific gene targets/pathways driving the invasive phenotype to develop more effective therapeutics. Here we show that UBASH3B (ubiquitin associated and SH3 domain containing B), a protein tyrosine phosphatase, is overexpressed in TNBC, where it supports malignant growth, invasion and metastasis in large through modulating EGFR. We also show that UBASH3B is a functional target of anti-invasive miR-200a that is downregulated in TNBC. Importantly, the oncogenic potential of UBASH3B is dependent on its tyrosine phosphatase activity, which targets CBL ubiquitin ligase for dephosphorylation and inactivation, leading to EGFR upregulation. Thus, UBASH3B may function as a crucial node in bridging multiple invasion-promoting pathways, thus providing a potential new therapeutic target for TNBC. Breast cancer tissues and breast cancer cell lines
Project description:Triple-negative breast cancer (TNBC) is characterized by lack of receptors, estrogen (ER), progesterone, and Her2, and standard receptor-targeted therapies are ineffective. FOXC1, a transcriptional factor aberrantly overexpressed in many cancers, drives growth, metastasis, and stem-cell-like properties in TNBC. However, the molecular function of FOXC1 is unknown, partly due to heterogeneity of TNBC. Here, we show that although FOXC1 regulates many cancer hallmarks in TNBC, its function is varied in different cell lines, highlighted by the differential response to CDK4/6 inhibitors upon FOXC1 loss. Despite this functional heterogeneity, we show that FOXC1 regulates key oncogenes and tumor suppressors and identify a set of core FOXC1 peaks conserved across TNBC cell lines. We identify the ER-associated and drug-targetable nuclear receptor NR2F2 as a cofactor of FOXC1. Finally, we show that core FOXC1 targets in TNBC are parallelly regulated by the pioneer factor FOXA1 and the nuclear receptor NR2F2 in ER+ breast cancer.
Project description:Triple negative breast cancer (TNBC) is an aggressive clinical phenotype, and accounts for 15% to 20% of all breast cancers. The molecular determinants of malignant cell behaviors in TNBC remain largely unknown. We find that the AP-1 transcription factor component, Fra-1, is overexpressed in basal-like breast tumors, and its expression level has high prognostic significance. Depletion of Fra-1 or its heterodimeric partner c-Jun inhibits the proliferative and invasive phenotypes in TNBC cells. To gain insights into the transcriptional regulatory networks of AP-1 in TNBC cells, we combine genome-wide ChIP-seq with loss-of-function transcriptome analyses. We observe dysregulation of direct targets of the Fra-1/c-Jun heterodimer involved in cell proliferation, cell adhesion, and cell-cell contact. Intriguingly, we find that AP-1 mediates downregulation of E-cadherin through direct transcriptional induction of ZEB2. This work sheds light on the mechanisms and pathways by which TNBC acquires invasiveness and proliferative propensity. BT549 cells grown in complete medium were transfected with a control siRNA, siRNA targeting Fra-1 or siRNA targeting c-Jun for 72 h, and then global gene expression profiles were assessed. Three or four biological replicates were used for each group.
Project description:Recent meta-analyses suggest triple-negative breast cancer (TNBC) is a heterogenous disease. In this study we sought to define these TNBC subtypes and identify subtype-specific markers and targets. We identified and confirmed four distinct, stable TNBC subtypes: (1) Luminal-AR (LAR); 2) Mesenchymal (MES); 3) Basal-Like Immune-Suppressed (BLIS), and 4) Basal-Like Immune-Activated (BLIA). RNA profiling analysis was conducted on 198 TNBC tumors (ER-negativity defined as Allred Scale value â¤2) with >50% cellularity (discovery set: n=84; validation set: n=114)
Project description:Triple-Negative Breast Cancer (TNBC) has a poor prognosis and adverse clinical outcomes among all breast cancer subtypes as there is no available targeted therapy. Overexpression of Enhancer of zeste homolog 2 (EZH2) has been shown to correlate with TNBC's poor prognosis, but the contribution of EZH2 catalytic (H3K27me3) versus non-catalytic EZH2 (NC-EZH2) function in TNBC progression remains elusive. We reveal that selective hyper-activation of functional EZH2 (H3K27me3) over NC-EZH2 alters TNBC metastatic landscape and fosters its peritoneal metastasis, particularly splenic. Instead of H3K27me3-mediated repression of gene expression; here, it promotes KRT14 transcription by attenuating binding of repressor Sp1 to its promoter. Further, KRT14 loss significantly reduces TNBC migration, invasion, and peritoneal metastasis. Consistently, human TNBC metastasis displays positive correlation between H3K27me3 and KRT14 levels. Finally, EZH2 knockdown or H3K27me3 inhibition by EPZ6438 reduces TNBC peritoneal metastasis. Altogether, our preclinical findings suggest a rationale for targeting TNBC with EZH2 inhibitors.