Pattern of expression of genes linked to epigenetic silencing in human breast cancer☆

Munot, Kailas; Bell, Sandra; Lane, Sally; Horgan, Kieran; Hanby, Andrew M.; Speirs, Valerie

doi:10.1016/j.humpath.2006.04.013

Cited by 40 publications

(37 citation statements)

References 32 publications

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“…Cells were plated on plastic dishes, and the culture medium was replaced every 2 days. For cell growth analysis the cells were cultured at a density of 1x10 4 DAPI staining of nuclei. The morphological changes in the nuclear chromatin of the cells undergoing apoptosis were detected by staining with the DNA-binding fluorochrome, 4',6-diamidino-2-phenylindole (DAPI).…”

Section: Methodsmentioning

confidence: 99%

“…The activated Ras protein contributes to several aspects of the malignant phenotype, including the deregulation of tumor cell growth, programmed cell death, invasiveness, and angiogenesis (3). Although ras mutations are rarely observed in breast cancers (<5%), there is considerable experimental evidence showing that aberrant ras-mediated signaling may promote the development of breast cancer (4).…”

Section: Introductionmentioning

confidence: 99%

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Effects of apicidin, a histone deacetylase inhibitor, on the regulation of apoptosis in H-ras-transformed breast epithelial cells

Park

Im²,

Kim³

et al. 2008

Int J Mol Med

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Abstract. The cellular susceptibility of cancer cells to histone deacetylase (HDAC) inhibitors is increased by the etopic expression of oncogenic Ras. However, the ability of HDAC inhibitors to regulate the apoptotic pathway in human breast cancer cells is still not completely understood. In this study, the anti-proliferative effects of apicidin were compared in Hras-transformed human breast epithelial (MCF10A-ras) and non-transformed epithelial (MCF10A) cells. MCF10A-ras cells showed a significantly higher growth rate than MCF10A cells. Apicidin significantly increased the levels of acetylated histone H3 and H4 in both cell lines. Western blot analysis and flow cytometry were used to determine if the anti-proliferative effects of apicidin in MCF10A and MCF10A-ras cells could be mediated by modulating the cell cycle. Apicidin attenuated the expression of cyclin E and CDK2 in MCF10A cells, decreased cyclin D1 and cyclin E levels in MCF10A-ras cells, and increased the levels of CDK inhibitors, p21WAF1/Cip1 and p27Kip1 , in both cell lines. Notably, the levels of hyperphosphorylation of the Rb protein levels were lower in the MCF10A-ras cells after apicidin treatment. Studies on the regulation of apoptosis showed that apicidin induces the upregulation of p53 and the downstream activation of ERK in MCF10A-ras cells. The up-regulation of p53 promoted Bax expression leading to activation of caspases-9 and -6, and eventually to apoptosis in MCF10A-ras cells. In addition, apicidin significantly increased the levels of ERK1/2 phosphorylation in MCF10A-ras cells. Therefore, the apicidinmediated ERK pathway appears to play an important role in modulating the pro-apoptotic pathway in MCF10A-ras cells.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects of apicidin, a histone deacetylase inhibitor, on the regulation of apoptosis in H-ras-transformed breast epithelial cells

Park

Im²,

Kim³

et al. 2008

Int J Mol Med

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“…We used an early-stage prostate cancer cell line (LNCaP) to derive mtDNA-depleted cells, mtDNA-reduced cells, and mtDNA-recovered cells and investigated the methylation status of CpG islands within promoters of endothelin B receptor (EDNRB), Ecadherin (CDH1), and O 6 -methylguanine-DNA methyltransferase (MGMT). We chose these genes because hypermethylation of the promoter CpG islands of these genes was induced in advanced form of cancer [7][8][9] but not in the early-stage prostate cancer, such as in LNCaP. Our results indicated that mtDNA content determines the CpG island hypermethylation pattern of the key cancer markers EDNRB, CDH-1, and MGMT and therefore identifies mtDNA as a key epigenetic factor affecting changes in prostate cancer progression.…”

Section: Introductionmentioning

confidence: 94%

Mitochondrial regulation of cancer associated nuclear DNA methylation

Xie

Naito

Mizumachi

et al. 2007

Biochemical and Biophysical Research Communications

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The onset and progression of cancer is associated with the methylation-dependent silencing of specific genes, however, the mechanism and its regulation have not been established. We previously demonstrated that reduction of mitochondrial DNA content induces cancer progression. Here we found that mitochondrial DNA-deficient LNρ0-8 activates the hypermethylation of the nuclear DNA promoters including the promoter CpG islands of the endothelin B receptor, O 6 -methylguanine-DNA methyltransferase, and E-cadherin. These are unmethylated and the corresponding gene products are expressed in the parental LNCaP containing mitochondrial DNA. The absence of mitochondrial DNA induced DNA methyltransferase 1 expression which was responsible for the methylation patterns observed. Inhibition of DNA methyltransferase eliminated hypermethylation and expressed gene products in LNρ0-8. These studies demonstrate loss or reduction of mitochondrial DNA resulted in the induction of DNA methyltransferase 1, hypermethylation of the promoters of endothelin B receptor, O 6 -methylguanine-DNA methyltransferase, and E-cadherin and reduction of the corresponding gene products.

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“…85 Loss of MGMT (O(6)-methylguanine-DNA methyltransferase) was found to be associated with DNA methylation in a subset of breast cancers. 86 Although DNMT3b, a de novo methyl transferase, is overexpressed in 30% of breast cancers, its expression alone was not considered to be a prognostic factor for breast cancer progression. 87 Such studies highlight the importance of identifying specific methylated genes for diagnostic purposes, and for monitoring the efficacy of therapeutic modalities.…”

Section: Dna Methylation and Breast Cancermentioning

confidence: 99%

DNA methylation in breast and colorectal cancers

2007

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DNA methylation is one of several epigenetic changes observed in cells. Aberrant methylation of tumor suppressor genes, proto-oncogenes, and vital cell cycle genes has led many scientists to investigate the underlying cellular mechanisms of DNA methylation under normal and pathological conditions. Although DNA methylation is necessary for normal mammalian embryogenesis, both hypo-and hypermethylation of DNA are frequently observed in carcinogenesis and other pathological disorders. DNA hypermethylation silences the transcription of many tumor suppressor genes, resulting in immortalization of tumor cells. The reverse process, demethylation and restoration of normal functional expression of genes, is augmented by DNA methylation inhibitors. Recent studies suggest that DNA hypomethylation may also control gene expression and chromosomal stability. However, the roles of and relationship between hypomethylation and hypermethylation are not well understood. This review provides a brief overview of the mechanism of DNA methylation, its relationship to extrinsic stimulation including dietary intake and aging, and of abnormally methylated DNA in breast and colorectal cancers, which could be used as prognostic and diagnostic markers.

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Pattern of expression of genes linked to epigenetic silencing in human breast cancer☆

Cited by 40 publications

References 32 publications

Effects of apicidin, a histone deacetylase inhibitor, on the regulation of apoptosis in H-ras-transformed breast epithelial cells

Effects of apicidin, a histone deacetylase inhibitor, on the regulation of apoptosis in H-ras-transformed breast epithelial cells

Mitochondrial regulation of cancer associated nuclear DNA methylation

DNA methylation in breast and colorectal cancers

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