Oncosuppressive role of p53-induced miR-205 in triple negative breast cancer.
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ABSTRACT:
SUBMITTER: Piovan C
PROVIDER: S-EPMC3679926 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Tumor necrosis factor alpha-induced protein 8 (TNFAIP8) is implicated in the tumor progression and prognosis of triple-negative breast cancer (TNBC), but the detailed regulatory mechanism of TNFAIP8 in cisplatin tolerance in TNBC has not yet been investigated. TNFAIP8 was evidently upregulated in TNBC tumor tissues and cell lines. Knocking down TNFAIP8 led to impaired proliferation and elevated apoptosis of TNBC cells upon cisplatin (DDP) treatment. Mechanistic studies revealed that TNFAIP8 repressed the expression of p53 and p53-promoted microRNA (miR)-205-5p; moreover, miR-205-5p targeted multiple genes required for the cell cycle and repressed Akt phosphorylation, which thus inhibited the proliferation of TNBC cells. In addition, silencing of TNFAIP8 led to the upregulation of miR-205-5p and the restraint of the TRAF2-NF-κB pathway, which thus enhanced the suppressive effects of DDP on tumor growth in nude mice. This study revealed that TNFAIP8 was essential in the DDP tolerance formation of TNBC cells by reducing p53-promoted miR-205-5p expression. Thus, targeting TNFAIP8 might become a promising strategy to suppress TNBC progression.
| S-EPMC7581818 | biostudies-literature
Project description:BackgroundOur previous study showed that CXCL11 could play an immunomodulatory role. In this study, we investigated the regulator (miR-205-3p) of CXCL11 and the mechanism of miR-205-3p as a tumor suppressor gene in gastric cancer (GC).Materials and methodsA target relationship between miR-205-3p and CXCL11 was revealed by using the bioinformatics method. This study detected the expressions of miR-205-3p and CXCL11 through qRT-PCR and Western blotting. Moreover, the expressions of Akt, PD-L1, p16, p21, and senescence-associated secretory phenotype (SASP) factor were determined. The effects of miR-205 on proliferation, invasion, and senescence of GC cells were assessed by using methods, such as transfection, Transwell assay, tablet cloning, flow cytometry, and senescence-associated beta-galactosidase (SA-β-gal) staining. Furthermore, the effects were verified using methods, like immunohistochemistry, flow cytometry and SA-β-gal in animal experiments.ResultsBased on the study, it is found that the expression of miR-205-3p is down-regulated, while that of CXCL11 is up-regulated in GC cell lines. By regulating CXCL11, miR-205-3p inhibits Akt activation, reduces the proliferation and invasion of GC cells, promotes cell apoptosis, induces senescence of GC cells, and secretes immunostimulatory SASP factor. The animal experiments confirm that miR-205-3p promotes cell senescence, down-regulates the immunosuppressive signal induced by PD-L1, and promotes secretion of immunostimulatory SASP factor, so that more T cells are recruited in blood and tumors.ConclusionsThis study revealed the molecular mechanism of miR-205-3p in inhibiting proliferation and invasion and inducing senescence of GC cells by regulating CXCL11 and Akt pathways in animal and cell experiments.
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Project description:Inactivation of p53 contributes significantly to the dismal prognosis of breast tumors, most notably triple-negative breast cancers (TNBCs). How the relief from p53 tumor suppressive functions results in tumor cell aggressive behavior is only partially elucidated. In an attempt to shed light on the implication of microRNAs in this context, we discovered a new signaling axis involving p53, miR-30a and ZEB2. By an in silico approach we identified miR-30a as a putative p53 target and observed that in breast tumors reduced miR-30a expression correlated with p53 inactivation, lymph node positivity and poor prognosis. We demonstrate that p53 binds the MIR30A promoter and induces the transcription of both miRNA strands 5p and 3p. Both miR-30a-5p and -3p showed the capacity of targeting ZEB2, a transcription factor involved in epithelial-mesenchymal transition (EMT), tumor cell migration and drug resistance. Intriguingly, we found that p53 does restrain ZEB2 expression via miR-30a. Finally, we provide evidence that the new p53/miR-30a/ZEB2 axis controls tumor cell invasion and distal spreading and impinges upon miR-200c expression. Overall, this study highlights the existence of a novel axis linking p53 to EMT via miR-30a, and adds support to the notion that miRNAs represent key elements of the complex network whereby p53 inactivation affects TNBC clinical behavior.
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Project description:Coix Seed Oil (CSO) possesses a wide range of pharmacological activities. Kanglaite Injection, a commercial product of CSO, has been used clinically as an anticancer drug in China for decades. However, its molecular mechanisms on triple-negative breast cancer (TNBC) remains to be elucidated. In this study, the effect of CSO was evaluated on murine TNBC 4T1 cells and the orthotopic tumor-bearing mouse model and underlying mechanisms were explored. CSO suppressed cell proliferation, colony formation in vitro, and tumor growth in vivo. miR-205-5p was substantially altered in CSO treated tumor tissues compared to the control group by miRNA-sequencing analysis. Sphingomyelin metabolism (SM) decreased in serum in model group compared to the control group, while it increased by CSO administration by lipid metabolomics analysis. The expression of sphingosine 1 phosphate receptor 1 (S1PR1), the critical effector of SM, was downregulated upon CSO treatment. Mechanically, miRNA-205 directly targeted S1PR1 to regulate SM and cell proliferation. CSO reduced the expression of S1PR1, cyclinD1, and phosphorylation levels of STAT3, MAPK, and AKT while upregulated p27. These results revealed that CSO exerted an anti-TNBC effect via the miR-205/S1PR1 axis to regulate sphingomyelin metabolism, and the downstream STAT3/MAPK/AKT signal pathways were partly involved.
| S-EPMC7556270 | biostudies-literature
Project description:Triple-negative breast cancer (TNBC) is characterized by poor response to therapy and low overall patient survival. Recently, Estrogen Receptor beta (ERβ) has been found to be expressed in a fraction of TNBCs where, because of its oncosuppressive actions on the genome, it represents a potential therapeutic target, provided a better understanding of its actions in these tumors becomes available. To this end, the cell lines Hs 578T, MDA-MB-468 and HCC1806, representing the claudin-low, basal-like 1 and 2 TNBC molecular subtypes respectively, were engineered to express ERβ under the control of a Tetracycline-inducible promoter and used to investigate the effects of this transcription factor on gene activity. The antiproliferative effects of ERβ in these cells were confirmed by multiple functional approaches, including transcriptome profiling and global mapping of receptor binding sites in the genome, that revealed direct negative regulation by ERβ of genes, encoding for key components of cellular pathways associated to TNBC aggressiveness representing novel therapeutic targets such as angiogenesis, invasion, metastasis and cholesterol biosynthesis. Supporting these results, interaction proteomics by immunoprecipitation coupled to nano LC-MS/MS mass spectrometry revealed ERβ association with several potential nuclear protein partners, including key components of regulatory complexes known to control chromatin remodeling, transcriptional and post-transcriptional gene regulation and RNA splicing. Among these, ERβ association with the Polycomb Repressor Complexes 1 and 2 (PRC1/2), known for their central role in gene regulation in cancer cells, was confirmed in all three TNBC subtypes investigated, suggesting its occurrence independently from the cellular context. These results demonstrate a significant impact of ERβ in TNBC genome activity mediated by its cooperation with regulatory multiprotein chromatin remodeling complexes, providing novel ground to devise new strategies for the treatment of these diseases based on ligands affecting the activity of this nuclear receptor or some of its protein partners.
| S-EPMC7000115 | biostudies-literature
Project description:Cytotoxic chemotherapy remains the mainstay of treatment for triple-negative breast cancer (TNBC) despite the promise of new targeted and biologic agents. Many studies have shown significant benefit of chemotherapy in the neoadjuvant, adjuvant, and metastatic treatment of TNBC. Neoadjuvant chemotherapy studies have consistently reported higher response rates in TNBC than non-TNBC, and pathologic complete response has been shown to predict improved long-term outcomes for TNBC. Although the specific adjuvant regimens that may be most effective for TNBC are still being determined, third-generation chemotherapy regimens using dose dense or metronomic polychemotherapy are among the most effective tools presently available. The role of specific chemotherapy agents in the treatment of TNBC remains incompletely defined and warrants careful review to ensure that the most effective therapy is delivered while minimizing unnecessary toxicity. Platinum agents have seen renewed interest in TNBC based on a growing body of preclinical and clinical data suggesting encouraging activity. Taxanes and anthracyclines are active in TNBC and remain important agents but have not shown specific benefit over non-TNBC. Capecitabine has limited reported data in TNBC, but some reports suggest differential activity in TNBC compared with hormone receptor-positive breast cancer. TNBC is itself a heterogeneous group in which subgroups such as BRCA1 mutation carriers may have particular sensitivity to platinum agents and relatively less sensitivity to taxanes. Therefore, the identification of additional molecular biomarkers to predict response to specific chemotherapy is required to further improve treatment strategies with the current menu of chemotherapy options and future combinations with targeted therapies.
| S-EPMC2882502 | biostudies-literature
Project description:Familial triple-negative breast cancers are often linked to mutations in the BRCA1 tumor suppressor gene. In sporadic triple-negative breast cancers BRCA1 is frequently inactivated at the transcriptional level, and it has been reported that this inactivation may be brought about by promoter methylation. More recently, it was found that BRCA1 may also be regulated at the post-transcriptional level by miRNAs. Here, we explored the expression of putative BRCA1-regulating miRNAs in sporadic human triple-negative breast cancer cells.Nine sporadic human breast cancer-derived cell lines and one benign breast epithelium-derived cell line were assessed for their hormone receptor, growth factor receptor and cytokeratin status by immunocytochemistry. The expression of 5 selected miRNAs predicted to target BRCA1 was assessed using qRT-PCR in the 10 cell lines. In addition, expression profiles of 84 known breast cancer-associated miRNAs were established in these 10 cell lines using PCR Array and qRT-PCR, respectively. The putative role of pre-selected candidate miRNAs in breast cancer development was assessed through exogenous expression of these miRNAs and their anti-miRNAs ('antagomirs') in MDA-MB-231 and MCF7 breast cancer-derived cells.Based on our expression profiling results, four candidate miRNAs (miR-10b, miR-26a, miR-146a and miR-153) were selected as being potentially involved in triple-negative breast cancer development. Exogenous expression assays revealed that miR-10b and miR-26a, but not miR-146a, can down-regulate the expression of BRCA1 in both triple-negative MDA-MB-231 and luminal epithelial MCF7 breast cancer-derived cells, whereas miR-153 could down-regulate BRCA1 expression only in MCF7 cells. In silico analysis of The Cancer Genome Atlas (TCGA) data confirmed that miR-146a is significantly higher expressed in triple-negative breast tumors compared to other (non triple-negative) breast tumors.Our work provides evidence for the involvement of specific miRNAs in triple-negative breast cancer development through regulating BRCA1 expression.
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Project description:Triple-negative breast cancer (TNBC), a management of aggressive breast cancer, remains an unmet medical challenge. Although a wave of efforts had spurred to design novel therapeutic method of TNBC, unpredictable prognosis with lacking effective therapeutic targets along with the resistance to apoptosis seriously limited survival benefits. Ferroptosis is a non-apoptotic form of cell death that is induced by excessive lipid peroxidation, which provide an innovative way to combat cancer. Emerging evidence suggests that ferroptosis plays an important role in the treatment of TNBC cells. Herein, a novel ferroptosis nanomedicine was prepared by loading simvastatin (SIM), a ferroptosis drug, into zwitterionic polymer coated magnetic nanoparticles (Fe3O4@PCBMA) to improve the therapeutic effect of TNBC. The as-obtained Fe3O4@PCBMA-SIM nanoparticles demonstrated more cytotoxicity against MDA-MB-231 than MCF-7 due to the higher expression of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), which demonstrated that statins could effectively kill TNBC. Further experiments showed that SIM could inhibit the expression of HMGCR to downregulate the mevalonate (MVA) pathway and glutathione peroxidase 4 (GPX4), thereby inducing cancer cell ferroptosis. What's more, PCBMA endows Fe3O4@PCBMA longer blood circulation performance to enhance their accumulation at tumor sites. Given that Fe3O4 have proven for clinical applications by the U.S. Food and Drug Administration (FDA) and SIM could induce cancer cell ferroptosis, the developed Fe3O4@PCBMA-SIM nanosystem would have great potential in clinics for overcoming the drug resistance brought about by apoptotic drugs to cancer cells.
| S-EPMC8502296 | biostudies-literature
Project description:Emerging evidence suggests that BRCA1 pathway contributes to the behavior of sporadic triple negative breast cancer (TNBC), but little is known about the mechanisms underlying this association. Considering the central role that microRNAs (miRNAs) play in gene expression regulation, the aim of this study was to identify miRNAs specifically deregulated in TNBC and investigate their involvement in BRCA1 regulation. Using locked nucleic acid (LNA)-based microarrays, expression levels of 1919 miRNAs were measured in paraffin-embedded tissues from 122 breast tumors and 11 healthy breast tissue samples. Differential miRNA expression was explored among the main subtypes of breast cancer, and 105 miRNAs were identified as specific for triple negative tumors. In silico prediction revealed that miR-498 and miR-187-5p target BRCA1, and these results were confirmed by luciferase reporter assay. While miR-187-5p was found overexpressed in a luminal B cell line, miR-498 was highly expressed in a triple negative cell line, Hs578T, and its expression was negatively correlated with the levels of BRCA1. We functionally demonstrated that miR-498 inhibits BRCA1 in breast cancer cell lines, and showed that inhibition of miR-498 led to reduced proliferation in the triple negative cell line Hs578T. Our results indicate that miR-498 regulates BRCA1 expression in breast cancer and its overexpression could contribute to the pathogenesis of sporadic TNBC via BRCA1 downregulation.
| S-EPMC4991439 | biostudies-literature
Project description:Perou's molecular classification defines tumors that neither express hormone receptors nor overexpress HER2 as triple-negative (TN) tumors. These tumors account for approximately 15% of breast cancers. The so-called basaloid tumors are not always synonymous with TN tumors; they differ in the fact that they express different molecular markers, have a higher histologic grade, and have a worse prognosis. Clinically they occur in younger women as interval cancer, and the risk of recurrence is higher within the first 3 years. Distant recurrences in the brain and visceral metastases are more common than in hormone receptor-positive tumors. Therapeutically, despite being highly chemosensitive, their progression-free time is generally short. In terms of chemotherapeutic treatment, anthracyclines and taxanes are useful drugs, and high response rates have been described for the combination of ixabepilone-capecitabine and platinums. The combination with antiangiogenic drugs has also proven useful. A group of new drugs, poly-(ADP-ribose)-polymerase inhibitors, showed favorable results in TN tumors with BRCA mutation. There are currently several ongoing studies with new drugs including epidermal growth factor receptor inhibitors, c-kit inhibitors, Raf/Mek/Map kinase inhibitors and mTOR inhibitors.
| S-EPMC2972557 | biostudies-literature