DNA methylation signatures of breast cancer in peripheral T-cells

Parashar, Surabhi; Cheishvili, David; Mahmood, Niaz; Arakelian, Ani; Tanvir, Imrana; Khan, Haseeb Ahmed; Kremer, Richard; Mihalcioiu, Catalin; Szyf, Moshe; Rabbani, Shafaat A.

doi:10.1186/s12885-018-4482-7

Cited by 35 publications

(33 citation statements)

References 41 publications

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“…In previous studies, we have identified a DNA methylation signature in peripheral blood mononuclear cells and T cells in hepatocellular carcinoma (HCC) which distinguished HCC from chronic hepatitis B and C versus healthy controls [25]. Similarly, DNA methylation signature in T cells of breast cancer patients showed strong correlation with breast cancer progression compared to healthy controls [24].…”

Section: Introductionmentioning

confidence: 99%

“…Host immuno-surveillance plays an important role in the recognition and elimination of transformed and tumor cells [20][21][22]. T-cells are the most prominent component of this system that control tumor growth [20][21][22] and hence have the potential of being effective cancer biomarkers [23][24][25]. In previous studies, we have identified a DNA methylation signature in peripheral blood mononuclear cells and T cells in hepatocellular carcinoma (HCC) which distinguished HCC from chronic hepatitis B and C versus healthy controls [25].…”

Section: Introductionmentioning

confidence: 99%

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DNA methylation signatures of Prostate Cancer in peripheral T-cells

et al. 2020

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Background: Prostate Cancer (PCa) is the second most common cancer in men where advancements have been made for early detection using imaging techniques, however these are limited by lesion size. Immune surveillance has emerged as an effective approach for early detection and to monitor disease progression. In recent studies, we have shown that host peripheral blood immune cells undergo changes in DNA methylation in liver and breast cancer. Methods: In the current study, we examined the DNA methylation status of peripheral blood T cells of men with positive biopsy for PCa versus men with negative biopsy having benign prostate tissue, defined as controls. T cells DNA was isolated and subjected to Illumina Infinium methylation EPIC array and validated using Illumina amplicon sequencing and pyrosequencing platforms. Results: Differential methylation of 449 CG sites between control and PCa T cell DNA showed a correlation with Gleason score (p < 0.05). Two hundred twenty-three differentially methylated CGs between control and PCa (Δß +/− 10%, p < 0.05), were enriched in pathways involved in immune surveillance system. Three CGs which were found differentially methylated following DMP (Differentially methylated probes) analysis of ChAMP remained significant after BH (Benjamini-Hochberg) correction, of which, 2 CGs were validated. Predictive ability of combination of these 3 CGs (polygenic methylation score, PMS) to detect PCa had high sensitivity, specificity and overall accuracy. PMS also showed strong positive correlation with Gleason score and tumor volume of PCa patients. Conclusions: Results from the current study provide for the first-time a potential role of DNA methylation changes in peripheral T cells in PCa. This non-invasive methodology may allow for early intervention and stratification of patients into different prognostic groups to reduce PCa associated morbidity from repeat invasive prostate biopsies and design therapeutic strategy to reduce PCa associated mortality.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

DNA methylation signatures of Prostate Cancer in peripheral T-cells

et al. 2020

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“…Epigenetic modifications have a crucial impact on regulating gene expression. DNA methylation is the most widely studied feature involved in the development and progression of numerous cancers, including breast cancer (14)(15)(16)(17). DNA methyltransferases include DNMT1, DNMT2, and the DNMT3a/3b/3l.…”

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FEN1 mediates miR‐200a methylation and promotes breast cancer cell growthviaMET and EGFR signaling

Zeng

Zhao

et al. 2019

FASEB j.

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Flap endonuclease 1 (FEN1) is recognized as a pivotal factor in DNA replication, long‐patch excision repair, and telomere maintenance. Excessive FEN1 expression has been reported to be closely associated with cancer progression, but the specific mechanism has not yet been explored. In the present study, we demonstrated that FEN1 promoted breast cancer cell proliferation via an epigenetic mechanism of FEN1‐mediated up‐regulation of DNA methyltransferase (DNMT)1 and DNMT3a. FEN1 was proved to interact with DNMT3a through proliferating cell nuclear antigen (PCNA) to suppress microRNA (miR)‐200a‐5p expression mediated by methylation. Furthermore, miR‐200a‐5p was identified to repress breast cancer cell proliferation by inhibiting the expression of its target genes, hepatocyte growth factor (MET), and epidermal growth factor receptor (EGFR). Overall, our data surprisingly demonstrate that FEN1 promotes breast cancer cell growth via the formation of FENl/PCNA/DNMT3a complex to inhibit miR‐200a expression by DNMT‐mediated methylation and to recover the target genes expression of miR‐200a, MET, and EGFR. The novel epigenetic mechanism of FEN1 on proliferation promotion provides a significant clue that FEN1 might serve as a predictive biomarker and therapeutic target for breast cancer.—Zeng, X., Qu, X., Zhao, C., Xu, L., Hou, K., Liu, Y., Zhang, N., Feng, J., Shi, S., Zhang, L., Xiao, J., Guo, Z., Teng, Y., Che, X. FEN1 mediates miR‐200a methylation and promotes breast cancer cell growth via MET and EGFR signaling. FASEB J. 33, 10717–10730 (2019). http://www.fasebj.org

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“…The Illumina intensity data (IDAT) files from the microarray experiment were normalized with BMIQ 32 and processed using the ChAMP 33 package as described by us before. 34 The methylation levels were obtained as β values that ranged from zero to one ('0' = fully unmethylated probe and '1' = fully methylated probe). Probes with single nucleotide polymorphism (SNP) were removed from the downstream analysis.…”

Section: Dna Isolation and Methylationepic 850 K Beadchip Microarraymentioning

confidence: 99%

S‐adenosylmethionine in combination with decitabine shows enhanced anti‐cancer effects in repressing breast cancer growth and metastasis

Mahmood

Arakelian

Cheishvili

et al. 2020

J Cellular Molecular Medi

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Abnormal DNA methylation orchestrates many of the cancer‐related gene expression irregularities such as the inactivation of tumour suppressor genes through hypermethylation as well as activation of prometastatic genes through hypomethylation. The fact that DNA methylation abnormalities can be chemically reversed positions the DNA methylation machinery as an attractive target for anti‐cancer drug development. However, although in vitro studies suggested that targeting concordantly hypo‐ and hypermethylation is of benefit in suppressing both oncogenic and prometastatic functions of breast cancer cells, this has never been tested in a therapeutic setting in vivo. In this context, we investigated the combined therapeutic effects of an approved nutraceutical agent S‐adenosylmethionine (SAM) and FDA‐approved hypomethylating agent decitabine using the MDA‐MB‐231 xenograft model of breast cancer and found a pronounced reduction in mammary tumour volume and lung metastasis compared to the animals in the control and monotherapy treatment arms. Immunohistochemical assessment of the primary breast tumours showed a significantly reduced expression of proliferation (Ki‐67) and angiogenesis (CD31) markers following combination therapy as compared to the control group. Global transcriptome and methylome analyses have revealed that the combination therapy regulates genes from several key cancer‐related pathways that are abnormally expressed in breast tumours. To our knowledge, this is the first preclinical study demonstrating the anti‐cancer therapeutic potential of using a combination of methylating (SAM) and demethylating agent (decitabine) in vivo. Results from this study provide a molecularly founded rationale for clinically testing a combination of agents targeting the epigenome to reduce the morbidity and mortality from breast cancer.

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DNA methylation signatures of breast cancer in peripheral T-cells

Cited by 35 publications

References 41 publications

DNA methylation signatures of Prostate Cancer in peripheral T-cells

DNA methylation signatures of Prostate Cancer in peripheral T-cells

FEN1 mediates miR‐200a methylation and promotes breast cancer cell growthviaMET and EGFR signaling

S‐adenosylmethionine in combination with decitabine shows enhanced anti‐cancer effects in repressing breast cancer growth and metastasis

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