Prevalence and Clinicopathologic Correlates of O6-Methylguanine-DNA Methyltransferase Methylation Status in Patients With Triple-Negative Breast Cancer Treated Preoperatively by Alkylating Drugs

2014 ◽  
Vol 14 (4) ◽  
pp. 285-290 ◽  
Author(s):  
Caterina Fumagalli ◽  
Silvia Della Pasqua ◽  
Vincenzo Bagnardi ◽  
Anna Cardillo ◽  
Andrea Sporchia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Dna Methyltransferase ◽  
Triple Negative ◽  
Methylation Status ◽  
Methylguanine Dna Methyltransferase ◽  
Alkylating Drugs

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 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 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.

Sign in / Sign up

Export Citation Format

Share Document