scholarly journals DNA methyltransferase expression in triple-negative breast cancer predicts sensitivity to decitabine

2018 ◽  
Vol 128 (6) ◽  
pp. 2376-2388 ◽  
Author(s):  
Jia Yu ◽  
Bo Qin ◽  
Ann M. Moyer ◽  
Somaira Nowsheen ◽  
Tongzheng Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Dna Methyltransferase ◽  
Triple Negative

scholarly journals Targeting DNA methylation for treating triple-negative breast cancer

2019 ◽  
Vol 20 (16) ◽  
pp. 1151-1157 ◽  
Author(s):  
Jia Yu ◽  
Jacqueline Zayas ◽  
Bo Qin ◽  
Liewei Wang
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Tumor Suppressor ◽  
Triple Negative Breast Cancer ◽  
Targeted Therapies ◽  
Tumor Suppressor Genes ◽  
Dna Methyltransferase ◽  
Triple Negative ◽  
Suppressor Genes ◽  
Dna Methyltransferase Inhibitors

Triple-negative breast cancer (TNBC) accounts for 15–20% of all invasive breast cancers and tends to have aggressive histological features and poor clinical outcomes. Unlike, estrogen receptor- or HER2-positive diseases, TNBC patients currently lack the US FDA-approved targeted therapies. DNA methylation is a critical mechanism of epigenetic modification. It is well known that aberrant DNA methylation contributes to the malignant transformation of cells by silencing critical tumor suppressor genes. DNA methyltransferase inhibitors reactivate silenced tumor suppressor genes and result in tumor growth arrest, with therapeutic effects observed in patients with hematologic malignancies. The antitumor effect of these DNA methyltransferase inhibitors has also been explored in solid tumors, especially in TNBC that currently lacks targeted therapies.

scholarly journals MYC suppresses STING-dependent innate immunity by transcriptionally upregulating DNMT1 in triple-negative breast cancer

2021 ◽  
Vol 9 (7) ◽  
pp. e002528
Author(s):  
Si-Yu Wu ◽  
Yi Xiao ◽  
Jin-Li Wei ◽  
Xiao-En Xu ◽  
Xi Jin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Innate Immunity ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Dna Methyltransferase ◽  
Triple Negative ◽  
Cell Function ◽  
In Vivo Studies

BackgroundTriple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and lacks definite treatment targets. Tumor immune microenvironment (TIME) heterogeneity has a profound impact on the immunotherapy response. Tumors with non-inflamed TIME derive limited benefit from immunotherapy. However, what drives the formation of the non-inflamed TIME in TNBC remains unclear.MethodsUsing our multiomics database of TNBC, we conducted an analysis to explore the key genomic events driving the formation of the non-inflamed TIME in TNBC. In vitro and in vivo studies further revealed potential mechanisms and the efficacy of combination treatment with immunotherapy.ResultsWith transcriptomic and genomic data, we systematically analyzed the TIME of TNBC and revealed that the classical basal-like subtype of TNBC consisted of two distinct microenvironment phenotypes, defined as the ‘inflamed’ and ‘non-inflamed’ subtypes. We performed further screening and demonstrated that MYC amplification and overexpression led to low immune infiltration and cytolytic activity in TIME. Mechanistically, MYC bound to DNMT1 promoter and activated DNMT1 transcription in TNBC cells, thus suppressing the Cyclic GMP-AMP synthase (cGAS)-STING pathway via an epigenetic regulatory way. In MYC-overexpressing TNBC, decitabine, an Food and Drug Administration (FDA)-approved DNA methyltransferase inhibitor, converted tumors from non-inflamed to inflamed tumors by enhancing T cell infiltration. Furthermore, the combination of decitabine with programmed cell death protein 1 (PD-1) inhibitor reversed T cell exhaustion and improved T cell function in mouse models, which elicited potent antitumor activity in MYC-overexpressing TNBC.ConclusionsOur work elucidates that the classic oncogene MYC induces immune evasion by repressing innate immunity. Furthermore, we provide a rationale for combining DNA methyltransferase inhibition with immunotherapy for the treatment of MYC-overexpressing TNBC.

scholarly journals Liquiritigenin decreases tumorigenesis by inhibiting DNMT activity and increasing BRCA1 transcriptional activity in triple-negative breast cancer

2020 ◽  
pp. 153537022095725
Author(s):  
Fang Liang ◽  
Hao Zhang ◽  
Hui Gao ◽  
Duo Cheng ◽  
Nan Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Dna Methyltransferase ◽  
Transcriptional Activity ◽  
Triple Negative ◽  
Promising Candidate ◽  
Mrna And Protein Expression ◽  
Cellular Dna

As a selective estrogen receptor β agonist, the natural flavonoid liquiritigenin reportedly inhibits invasiveness of breast cancer cells, but its specific role and mechanism remain largely unclear. In this study, cells from the triple negative breast cancer lines MDA-MB-231 and BT549 were incubated with different concentrations of liquiritigenin. The results indicated that low concentrations had no significant cytotoxic effect, whereas high concentrations decreased viability of both MDA-MB-231 and BT549 cells. Liquiritigenin treatment also resulted in increased apoptosis and enhanced Caspase3 activity. After liquiritigenin treatment, we observed decreased invasive and migratory capacities of cells, as well as upregulated E-cadherin and downregulated N-cadherin, vimentin, and MMP9. Interestingly, liquiritigenin increased the mRNA and protein expression of breast cancer 1 (BRCA1). It also increased p21 and growth arrest and DNA-damage-inducible 45 alpha (GADD45A) levels, accompanied by decreased cellular DNA methyltransferase (DNMT) activity and downregulation of DNMT1, DNMT3a, and DNMT3b. These findings suggest that liquiritigenin can inhibit malignant behavior of triple negative breast cancer cells by inhibiting DNMT activity and increasing BRCA1 expression and its transcriptional activity. Liquiritigenin thus may be a promising candidate for the treatment of breast cancer. Impact statement Triple negative breast cancer (TNBC) is an aggressive cancer with a poor prognosis and higher metastatic rates and relapse frequencies than other breast cancers. Natural flavonoid liquiritigenin reportedly inhibits invasiveness of TNBC MDA-MB-231 cells, but its specific role and mechanism remain unclear. This study administered different doses of liquiritigenin into TNBC cell lines MDA-MB-231 and BT549, and found that it hindered cell proliferation, increased apoptosis, and repressed cell invasion and migration. BRCA1 exerts multiple functions and is closely related to the occurrence and development of breast cancer. Interestingly, the mRNA and protein expression of BRCA1 increased after liquiritigenin administration. Liquiritigenin also upregulated two downstream genes of BRCA1 (p21 and DNA-damage-inducible 45 alpha), decreased cellular DNA methyltransferase (DNMT) activity, and reduced BRCA1 promoter methylation. Thus, liquiritigenin may be a promising candidate for the treatment of TNBC due to its inhibition of DNMT activity and upregulation of BRCA1.

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