Epigenetic Therapy for Breast Cancer

Cai, Fengfeng; Kohler, Corina; Zhang, Bei; Wang, Minghong; Chen, Weijie; Zhong, Xiaoyan

doi:10.3390/ijms12074465

Cited by 35 publications

(35 citation statements)

References 72 publications

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Section: Discussionmentioning

confidence: 99%

“…[44][45][46] DNMT and histone deacetylases (HDAC) have become the primary targets for the epigenetic regulation of cancer. 45,46 If DNMT and HDAC inhibitors act by reactivating TSGs, DNA methylation status may be used as a biomarker to predict response to treatment with these drugs. 45 As basal-like subtype of breast cancer or breast cancer with stem cell phenotype was found to be less methylated in the genes involved in breast cancer progression, the agents that modulate epigenetic changes may be less effective in those cases.…”

Section: Discussionmentioning

confidence: 99%

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Distinct patterns of promoter CpG island methylation of breast cancer subtypes are associated with stem cell phenotypes

et al. 2012

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Although DNA methylation profiles in breast cancer have been connected to breast cancer molecular subtype, there have been no studies of the association of DNA methylation with stem cell phenotype. This study was designed to evaluate the promoter CpG island methylation of 15 genes in relation to breast cancer subtype, and to investigate whether the patterns of CpG island methylation in each subtype are associated with their cancer stem cell phenotype represented by CD44 þ /CD24À and ALDH1 expression. We performed MethyLight analysis of the methylation status of 15 promoter CpG island loci involved in breast cancer progression (APC, DLEC1, GRIN2B, GSTP1, HOXA1, HOXA10, IGF2, MT1G, RARB, RASSF1A, RUNX3, SCGB3A1, SFRP1, SFRP4, and TMEFF2) and determined cancer stem cell phenotype by CD44/CD24 and ALDH1 immunohistochemistry in 36 luminal A, 33 luminal B, 30 luminal-HER2, 40 HER2 enriched, and 40 basal-like subtypes of breast cancer. The number of CpG island loci methylated differed significantly between subtypes, and was highest in the luminal-HER2 subtype and lowest in the basal-like subtype. Methylation frequencies and levels in 12 of the 15 genes differed significantly between subtypes, and the basal-like subtype had significantly lower methylation frequencies and levels in nine of the genes than the other subtypes. CD44 þ /CD24À and ALDH1 þ putative stem cell populations were most enriched in the basal-like subtype. Methylation of promoter CpG islands was significantly lower in CD44 þ /CD24-cell ( þ ) tumors than in CD44 þ /CD24-cell (À) tumors, even within the basallike subtype. ALDH1 ( þ ) tumors were also less methylated than ALDH1 (À) tumors. Our findings showed that promoter CpG island methylation was different in relation to breast cancer subtype and stem cell phenotype of tumor, suggesting that breast cancers have distinct patterns of CpG island methylation according to molecular subtypes and these are associated with different stem cell phenotypes of the tumor.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Distinct patterns of promoter CpG island methylation of breast cancer subtypes are associated with stem cell phenotypes

et al. 2012

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“…As epigenetic alterations are reversible, DNA methyltransferases represent potential targets for epigenetic therapy using DNMT inhibitors (Egger et al, 2004;Cai et al, 2011). This study is the first to evaluate associations between the polymorphisms of 5 DNMTs and breast cancer in populations of South China.…”

Section: Discussionmentioning

confidence: 99%

Association of DNMT1 and DNMT3B polymorphisms with breast cancer risk in Han Chinese women from South China

Sun¹,

Yang²,

Xu³

et al. 2012

Genet. Mol. Res.

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ABSTRACT. Patterns of DNA methylation are established and maintained by a family of DNA methyltransferases (DNMTs). Aberrant promoter DNA methylation of tumor suppressor genes is found in breast cancer. Association studies between DNMT gene polymorphisms and breast cancer in various populations have reported inconsistent results. This study assessed the associations of single nucleotide polymorphisms (SNPs) in DNMT1, DNMT3A, DNMT3B, DNMT3L, and DNMT2 with breast cancer among Han Chinese women from South China. Sixteen SNPs (rs2114724, rs2228611, rs2228612, rs8101866, and rs16999593 in DNMT1; rs13420827, rs11887120, rs13428812, rs1550117, rs11695471, and rs6733301 in DNMT3A; rs2424908, rs2424913, and rs6087990 in DNMT3B; rs113593938 in DNMT3L, and rs11254413 in DNMT2) in 408 women with breast cancer and 469 controls were genotyped using a MassARRAY matrix-assisted laser desorption/ ionization time-of-flight mass spectrometry platform. Two SNPs, Polymorphisms of DNMT1 and DNMT3B and breast cancer risk rs16999593 in DNMT1 and rs2424908 in DNMT3B, were significantly associated with breast cancer risk. The heterozygous genotype CT of rs16999593 was associated with increased breast cancer risk [odds ratio (OR) = 1.60; 95% confidence interval (95%CI) = 1.20-2.14; P = 0.0052], whereas rs2424908 was associated with decreased risk (OR = 0.62; 95%CI = 0.46-0.84; P = 0.0061). Other DNMT polymorphisms showed no significant associations with breast cancer risk in the study population. Haplotype CGTC of rs2114724, rs2228611, rs8101866, and rs16999593 in DNMT1 differed significantly as a risk factor between the case and control groups (OR = 1.51; 95%CI = 1.18-1.93; P = 0.0012). The heterozygous genotypes of rs16999593 in DNMT1 and rs2424908 in DNMT3B were strongly associated with breast cancer risk.

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“…These molecules have theoretical advantages as the DNA incorporation requirement of nucleoside analogs makes these drugs exquisitely S-phase specific, a considerable barrier in some malignancies [156]. Small molecules may have selective inhibition of DNMTs and are in that way considered more useful than nucleoside analogues [159]. In addition, small changes in their structure (e.g.…”

Section: Other (Non-nucleoside Analogues)mentioning

confidence: 99%