DNA hypomethylation in breast cancer: An independent parameter of tumor progression?

Bernardino, Jacqueline; Roux, Cecilia; Almeida, Anna; Vogt, Nicolas; Gibaud, Anne; Gerbault-Seureau, M.; Magdelénat, H.; Bourgeois, Claire A.; Malfoy, Bernard; Dutrillaux, Bernard

doi:10.1016/s0165-4608(96)00385-8

Cited by 76 publications

(54 citation statements)

References 21 publications

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“…Other alterations of the DNA methylation machinery have been already observed in breast cancers but, as described in this study for the expression of the MBDs, no correlation between the global DNA methylation status and clinical or biological parameters has been observed (Bernardino et al, 1997). As suggested for the involvement of DNA hypomethylation in breast cancers (Bernardino et al, 1997), the variation of MBDs expression level might represent an independent parameter of tumor progression.…”

Section: Discussionmentioning

confidence: 39%

“…As suggested for the involvement of DNA hypomethylation in breast cancers (Bernardino et al, 1997), the variation of MBDs expression level might represent an independent parameter of tumor progression. More recently, an overall deregulation of the DNA methylation control, during esophageal carcinogenesis, has also been suggested from the analysis of a large number of CpG islands (Eads et al, 2001).…”

Section: Discussionmentioning

confidence: 94%

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MeCP2 and MBD2 expression during normal and pathological growth of the human mammary gland

et al. 2002

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During the last years, a direct link between DNA methylation and repressive chromatin structure has been established. This structural modi®cation is mediated by histone deacetylases targeted to the methylated sequences by Methyl Binding Proteins (MBD). Human cancer cells exhibit both a global hypomethylation and some localized hypermethylations suggesting that the deregulation of the methylation machinery is a central event in tumorigenesis. Therefore, we have investigated in human tissues the expression of two major MBDs, MeCP2 and MBD2, during the proliferation of normal breast and in benign and neoplasic breast tumors. Quantitation of the transcripts indicates that MBD2 mRNAs are 20 ± 30-fold more abundant than MeCP2 transcripts in the adult and fetal human mammary gland. In pathological tissues samples MBD2 mRNA levels are signi®cantly higher (P=0.001) in benign tumors compared with normal breast tissues, whereas MeCP2 expression is not modi®ed in these specimens. In neoplasic samples a deregulation of the expression of both genes was found. The amounts of MBD2 and MeCP2 transcripts vary greatly between samples in cancer cells compared to normal breast tissues or benign tumors, and in invasive ductal carcinomas the amount of MBD2 mRNA is signi®cantly (P=0.03) associated with the tumor size. Taken together these data suggest that upregulation of MBD2 might be associated with breast cell proliferation. In line with this hypothesis MBD2 is also upregulated during the prenatal development of the human mammary gland, but in contrast to that observed in tumor cells, MeCP2 is also coordinately upregulated in the fetal breast tissues, suggesting that deregulation of MeCP2 and MBD2 occurs in human breast cancers.

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Section: Discussionmentioning

confidence: 39%

Section: Discussionmentioning

confidence: 94%

MeCP2 and MBD2 expression during normal and pathological growth of the human mammary gland

et al. 2002

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“…[11][12][13] Long interspersed nucleotide element-1 (LINE-1) is a major constituent of repetitive transposable elements in the human genome. 14 There are approximately 500,000 copies of LINE-1 across the human genome, occurring as hypermethylated sequences under physiologically normal conditions.…”

Section: Introductionmentioning

confidence: 99%

Associations between genetic variation in one-carbon metabolism and LINE-1 DNA methylation in histologically normal breast tissues

Llanos

Marian²,

Brasky

et al. 2015

Epigenetics

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Genome-wide DNA hypomethylation is an early event in the carcinogenic process. Percent methylation of long interspersed nucleotide element-1 (LINE-1) is a biomarker of genome-wide methylation and is a potential biomarker for breast cancer. Understanding factors associated with percent LINE-1 DNA methylation in histologically normal tissues could provide insight into early stages of carcinogenesis. In a cross-sectional study of 121 healthy women with no prior history of cancer who underwent reduction mammoplasty, we examined associations between plasma and breast folate, genetic variation in one-carbon metabolism, and percent LINE-1 methylation using multivariable regression models (adjusting for race, oral contraceptive use, and alcohol use). Results are expressed as the ratio of LINE-1 methylation relative to that of the referent group, with the corresponding 95% confidence intervals (CI). We found no significant associations between plasma or breast folate and percent LINE-1 methylation. Variation in MTHFR, MTR, and MTRR were significantly associated with percent LINE-1 methylation. Variant allele carriers of MTHFR A1289C had 4% lower LINE-1 methylation (Ratio 0.96, 95% CI 0.93-0.98), while variant allele carriers of MTR A2756G (Ratio 1.03, 95% CI 1.01-1.06) and MTRR A66G (Ratio 1.03, 95% CI 1.01-1.06) had 3% higher LINE-1 methylation, compared to those carrying the more common genotypes of these SNPs. DNA methylation of LINE-1 elements in histologically normal breast tissues is influenced by polymorphisms in genes in the one-carbon metabolism pathway. Future studies are needed to investigate the sociodemographic, environmental and additional genetic determinants of DNA methylation in breast tissues and the impact on breast cancer susceptibility.

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“…In the latter study, a small, but not statistically significant, increase in global m 5 C levels was observed in ductal carcinomas. In contrast, two other large-scale analyses of breast ductal carcinomas found significant global hypomethylation relative to normal breast tissue or benign breast lesions by analysis of patterns of HpaII-or MspI-digested DNA or in an in vitro methyl acceptor assay with SssI methyltransferase (Bernardino et al, 1997;Soares et al, 1999). In summary, global deficiencies in the genomic m 5 C content in various cancers vs control tissues are seen very much more often than overall increases in m 5 C levels in DNA, despite the frequent findings of localized hypermethylation in all the above types of cancers.…”

Section: Variety Of Cancers Displaying Dna Hypomethylationmentioning

confidence: 71%

DNA methylation in cancer: too much, but also too little

2002

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Cancer-associated DNA hypomethylation is as prevalent as cancer-linked hypermethylation, but these two types of epigenetic abnormalities usually seem to affect different DNA sequences. Much more of the genome is generally subject to undermethylation rather than overmethylation. Genomic hypermethylation in cancer has been observed most often in CpG islands in gene regions. In contrast, very frequent hypomethylation is seen in both highly and moderately repeated DNA sequences in cancer, including heterochromatic DNA repeats, dispersed retrotransposons, and endogenous retroviral elements. Also, unique sequences, including transcription control sequences, are often subject to cancer-associated undermethylation. The high frequency of cancer-linked DNA hypomethylation, the nature of the affected sequences, and the absence of associations with DNA hypermethylation are consistent with an independent role for DNA undermethylation in cancer formation or tumor progression. Increased karyotypic instability and activation of tumor-promoting genes by cis or trans effects, that might include altered heterochromatin-euchromatin interactions, may be important consequences of DNA hypomethylation which favor oncogenesis. The relationship of DNA hypomethylation to tumorigenesis is important to be considered in the light of cancer therapies involving decreasing DNA methylation. Inducing DNA hypomethylation may have short-term anticancer effects, but might also help speed tumor progression from cancer cells surviving the DNA demethylation chemotherapy.

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DNA hypomethylation in breast cancer: An independent parameter of tumor progression?

Cited by 76 publications

References 21 publications

MeCP2 and MBD2 expression during normal and pathological growth of the human mammary gland

MeCP2 and MBD2 expression during normal and pathological growth of the human mammary gland

Associations between genetic variation in one-carbon metabolism and LINE-1 DNA methylation in histologically normal breast tissues

DNA methylation in cancer: too much, but also too little

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