MGMT inhibition in ER positive breast cancer leads to CDC2, TOP2A, AURKB, CDC20, KIF20A, Cyclin A2, Cyclin B2, Cyclin D1, ERα and Survivin inhibition and enhances response to temozolomide

Bobustuc, George C.; Kassam, Amin; Rovin, Richard; Jeudy, Sheila; Smith, Joshua S.; Isley, Beth; Singh, Maharaj; Paranjpe, Ameya; Srivenugopal, Kalkunte S.; Konduri, Santhi D.

doi:10.18632/oncotarget.25696

Cited by 18 publications

(16 citation statements)

References 52 publications

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“…SKBR3 cell line used in our study is an ER-α − cell line in terms of characteristics. When compared to other studies [17] [19] in which the relation between ER-α and MGMT gene is revealed, the low expression of MGMT gene expression in SKBR3 cell line is seen to correlate with a low ER-α expression level. As a result of this characteristic of SKBR3 cell line, it is thought that the absence of ER-α expression leads to a low level of MGMT expression and therefore, a positive effect of TMZ treatment.…”

Section: Discussioncontrasting

confidence: 58%

“…The two-year survival rate was observed to be 26.5% in treatment with radiotherapy and TMZ, and 10.4% in radiotherapy alone [14]. In another study with breast cancer demonstrates that survival rates of MCF-7 cells, which has ER + character, decreased to 52% exposed to 644 µM TMZ treatment for 4 days [17].…”

Section: Discussionmentioning

confidence: 96%

“…It was observed that TMZ reduced the activity of MGMT protein by 90%. In addition, when MCF-7 cells were exposed to TMZ for 4 days, MGMT expression was inhibited by TMZ [17].…”

Section: Discussionmentioning

confidence: 99%

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The Evaluation of the Effects of Temozolomide on MGMT Gene Expression in MCF-7 and SKBR3 Human Breast Cancer Cell Lines

Eroğlu¹,

Sevim²

2019

JCT

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Background and Aim: In this study, it was aimed to examine the cytotoxic effect of temozolomide (TMZ) treatment, on MCF-7 and SKBR3 cell lines, to study the methylation levels of MGMT gene expression and gene promoter region. Methods: The MTT test was performed to determine the effective dose of TMZ. The time-dependent cell survival test was performed after the IC 50 value was found. Western blotting was performed to determine MGMT gene expression levels. High Resolution Melting (HRM) technique was used to determine the methylation levels of MGMT gene promoter region. Results: TMZ has been shown to have a high cytotoxic effect on SKBR3 cell line and low cytotoxicity on MCF-7. When MGMT expression levels before and after TMZ treatment were observed by western blotting, the gene expression levels of TMZ treatment were shown to decrease in both cell lines. It was observed that MGMT gene promoter region was hypermethylated in two cell lines, and that the application of TMZ further increased the methylation levels in the promoter region. Conclusions: It was seen that TMZ could be used as a single agent in SKBR-3 cell line. With this study on breast cancer, it is expected that temozolomide treatment will lead future in vitro and in vivo studies for breast cancer.

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Section: Discussioncontrasting

confidence: 58%

Section: Discussionmentioning

confidence: 96%

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The Evaluation of the Effects of Temozolomide on MGMT Gene Expression in MCF-7 and SKBR3 Human Breast Cancer Cell Lines

Eroğlu¹,

Sevim²

2019

JCT

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“…Another tumor-suppressor gene we studied was MGMT, which functions in DNA repair (49), and whose aberrant promoter hypermethylation has been shown in one-third of breast cancer cases (28). Contrary to the elevatin of methylation of RASSF1A, SFRP1 and DCC promoter in at least one HNO-adapted breast cancer cell line, we observed that methylation of MGMT promoter was significantly reduced in MCF-7-HNO cells compared to the parentaI cell line.…”

Section: Discussionmentioning

confidence: 65%

DNA Methylation in Human Breast Cancer Cell Lines Adapted to High Nitric Oxide

Demircan

Yücel

Radosevich

2019

In Vivo

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Background: Nitric oxide (NO) exposure has been suggested to cause alterations in DNA methylation in breast cancer. We investigated the effect of NO on DNA methylation of promoters in cell lines of breast cancer. Material and Methods: The methylation status of the promoters of breast cancer 1 (BRCA1), deleted in colon cancer (DCC), Rasassociation domain family 1A (RASSF1A), O 6-methylguanine-DNA methyltransferase (MGMT), and secreted frizzled related protein 1 (SFRP1) were analyzed in the parental and high nitric oxide-adapted cell lines of breast cancer using Illumina MiSequencing. Results: Methylation of RASSF1A promoter in BT-20-HNO (74.7%) was significantly higher than that in BT-20 cells (72%) (p<0.05), whereas in MCF-7-HNO cells, methylation of MGMT promoter was found to have significantly decreased as compared to its parental cell line (45.1% versus 50.1%; p<0.0001). Promoter methylation of SFRP and DCC was elevated in T-47D-HNO relative to its parent cell line (p<0.05). Conclusion: Similarly to the double-edged effects of NO on tumorigenesis, its epigenetic effects through DNA methylation are diverse and contradictory in breast cancer.

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“…KIF20A is found overexpressed at both the mRNA and protein levels than the normal counterparts in breast cancer [65][66][67] and also in several other cancers including gastric cancer [68], bladder cancer [69,70], pancreatic cancer [71][72][73], hepatocellular cancer [74], lung cancer [75], glioma [76], and melanoma [77]. The overexpression of KIF20A gene is significantly associated with the poor survival of breast cancer patient [65,66] and drug resistance [66,78].…”

Section: Gene Type Gene Namementioning

confidence: 99%

Uncovering missed indels by leveraging unmapped reads

Hasan

Zhang

2018

Preprint

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In current practice, Next Generation Sequencing (NGS) applications start with mapping/aligning short reads to the reference genome, with the aim of identifying genetic mutations. While most short reads can be mapped to the reference genome accurately by existing alignment tools, a significant number remain unmapped and excluded from downstream analyses thus potentially discarding important biological information hidden in the unmapped reads. This paper describes Genesis-indel, a computational pipeline that explores the unmapped reads to identify novel indels that are initially missed in the alignment procedure. Genesis-indel is applied to the unmapped reads of 30 Breast Cancer patients from TCGA. Results show that the unmapped reads are conserved between the two subtypes of breast cancer investigated in this study and might contribute to the divergence between the subtypes. Genesis-indel is able to leverage the unmapped reads to identify 72,997 small to large novel high-quality indels previously not found in the original alignments and among them, 16,141 have not been annotated in the widely used mutation database. Statistical analysis shows that these new indels mostly altered the oncogenes and tumor suppressor genes.Functional annotation further reveals that these indels are strongly correlated to pathways of cancer and can have high to moderate impact on protein functions. Additionally, these indels overlap with the genes that are missed in the indels from the originally mapped reads and contribute to the tumorigenesis in multiple carcinomas.

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MGMT inhibition in ER positive breast cancer leads to CDC2, TOP2A, AURKB, CDC20, KIF20A, Cyclin A2, Cyclin B2, Cyclin D1, ERα and Survivin inhibition and enhances response to temozolomide

Cited by 18 publications

References 52 publications

The Evaluation of the Effects of Temozolomide on MGMT Gene Expression in MCF-7 and SKBR3 Human Breast Cancer Cell Lines

The Evaluation of the Effects of Temozolomide on MGMT Gene Expression in MCF-7 and SKBR3 Human Breast Cancer Cell Lines

DNA Methylation in Human Breast Cancer Cell Lines Adapted to High Nitric Oxide

Uncovering missed indels by leveraging unmapped reads

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