High-density array analysis of DNA methylation in Tamoxifen-resistant breast cancer cell lines

Williams, Kristin E.; Anderton, Douglas L.; Lee, Maxwell P.; Pentecost, Brian T.; Arcaro, Kathleen F.

doi:10.4161/epi.27111

Cited by 26 publications

(37 citation statements)

References 23 publications

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“…Five gene regions are included on the HM450 BC: promoter (TSS200 and TSS1500 regions; sites 200 and 1500 bp upstream of the transcriptional start site respectively), 5′UTR/1st exon, body, 3′UTR, and intergenic (areas not included in the previous four regions and undefined in GenomeStudio, therefore they are not included in the pathway analyses) . In the case of multiple transcripts or gene overlap, a single CpG site (or MAPINFO coordinate in GenomeStudio) may represent multiple genes or gene regions . Panther Classification System (http://www.pantherdb.org) was used to conduct pathway analysis from the lists of genes associated with hyper‐ and hypomethylated dmCpGs.…”

Section: Methodsmentioning

confidence: 99%

DNA methylation in breast cancers: Differences based on estrogen receptor status and recurrence

Williams

Jawale

Schneider

et al. 2018

J of Cellular Biochemistry

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DNA methylation plays a role in the etiology of primary breast cancers. We analyzed paired primary and second breast tumors to elucidate the role of methylation in recurrence. Methylation profiles from paired primary and second breast tumors of 23 women were assessed using the HumanMethylation450 BeadChip. Twelve women had estrogen receptor positive (ERpos) primary and second tumors, five had estrogen receptor negative (ERneg) primary and second tumors, and six had an ERpos primary tumor but an ERneg second tumor. Stratifying tumors by occurrence revealed that the greater methylation previously associated with ERpos tumors, is more pronounced in primary tumors than in second tumors. Further, ERneg second tumors are more methylated than ERpos second tumors among women who had ERpos primary tumors. Pathway analyses using gene lists generated from comparisons of methylation in ERpos primary tumors from the paired sets with ERpos tumors from six women without recurrences, identified differences between groups based on the ER status of the second tumor. Hypermethylated genes of significantly enriched pathways were differentially associated with survival. DNA methylation profiles of ERpos primary breast tumors support the development and use of tumor methylation profiles for stratifying women with breast cancer both for prognosis and therapy.

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Section: Methodsmentioning

confidence: 99%

DNA methylation in breast cancers: Differences based on estrogen receptor status and recurrence

Williams

Jawale

Schneider

et al. 2018

J of Cellular Biochemistry

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“…Promoter hypermethylation which results in downregulation of drug‐metabolizing enzymes (cytochrome P450) also could lead to tamoxifen resistance (Widschwendter et al, ). In addition, methylation analyses have revealed that tamoxifen resistant cell lines share 3,000 hypermethylated CpGs (Williams, Anderton, Lee, Pentecost, & Arcaro, ). DNA methyltransferases (DNMTs) are a group of enzymes which are responsible for maintenance (DNMT1) and de novo (DNMT3A, DNMT3B) DNA methylation (Das & Singal, ).…”

Section: Introductionmentioning

confidence: 99%

Altered DNA methyltransferases promoter methylation and mRNA expression are associated with tamoxifen response in breast tumors

Jahangiri

Mosaffa

Razavi

et al. 2018

Journal Cellular Physiology

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Tamoxifen is a standard anti-hormone treatment in estrogen receptor positive breast carcinoma patients. Unfortunately, about 50% of patients relapse during treatment. Promoter hypermethylation contributes to the epigenetic modulation of tamoxifen resistance-related genes. To evaluate the contribution of DNMTs expression and their promoter methylation as diagnostic biomarkers in development of breast malignancy and tamoxifen resistance, the present study was designed and 107 breast tumors and normal breast tissues were recruited. Methylation-specific high-resolution melt curve analysis and quantitative RT-PCR were performed to evaluate DNMTs promoter methylation and mRNA expression, respectively. Our results indicated that DNMT3A and DNMT3B promoters were demethylated in breast tumors as compared to control tissues. The mRNA expression levels of all three DNMTs were significantly increased in tumor specimens in comparison to control tissues (p < 0.05). Among tumor tissues, DNMT3A promoter methylation was significantly higher in tamoxifen sensitive patients (p = 0.001). Overexpression of DNMT3A (p = 0.037) and DNMT3B (p < 0.001) mRNA were observed in tamoxifen resistance group. Multivariate logistic regression analysis indicated that low methylation status of DNMT3A and overexpression of DNMT3B could be as independent predictors of disease recurrence. Multivariate Cox regression analysis, revealed that high methylation status of DNMT3A could be an independent and favorable predictor for disease free survival (p = 0.002) and overall survival (p = 0.026); high expression of DNMT1 (p = 0.03) remained significant and unfavorable predictive factor for overall survival. In conclusion, our data for the first time indicated that low methylation status of DNMT3A promoter and overexpression of DNMT3B could contribute to disease recurrence in tamoxifen-treated breast cancer patients.

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“…Treatment with selective estrogen receptor modulators like tamoxifen and raloxifene have become the mainstay of this approach, with the optimal duration of adjuvant endocrine therapy currently at 5 y. However, this therapy is limited by the development of resistance; many groups are trying to understand the mechanisms behind this [7–11]. …”

Section: Introductionmentioning

confidence: 99%

Seven In Absentia Homolog 2 (SIAH2) downregulation is associated with tamoxifen resistance in MCF-7 breast cancer cells

Interiano

Yang

Harris

et al. 2014

Journal of Surgical Research

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Background A significant percentage of estrogen receptor (ER)–positive breast cancers are resistant to tamoxifen therapy. Seven in Absentia Homolog 2 (SIAH2), an E3 ubiquitin protein ligase, has been shown to be associated with resistance to antiestrogens. We sought to assess its role in the resistance of a breast cancer cell line, MCF-7, to the ER antagonist, tamoxifen. Materials and methods A bioinformatic approach was used for the analysis of SIAH2 expression in breast cancer. MCF-7 and MDA-MB-231, which are ER-positive and -negative breast cancer cell lines, respectively, were used for in vitro studies. SIAH2 and ER-α were selectively knocked down in these cell lines with small-interfering RNAs. Knockdowns were confirmed with Western blot analysis and quantitative real-time polymerase chain reaction. Cells with SIAH2 knockdown were treated with tamoxifen and compared with controls. Results Knockdown of SIAH2 followed by treatment with tamoxifen resulted in a significant decrease in the sensitivity of treated ER-positive cells. Of note, knockdown of SIAH2 resulted in downregulation of ER-α, whereas knockdown of ER-α had minimal effect on SIAH2. Consistent with this result, the bioinformatic analysis of clinical data revealed that SIAH2 expression is significantly correlated with ER positivity in human breast cancers, and low SIAH2 expression is associated with a poorer response to tamoxifen. Conclusions SIAH2 appears to be an important modulator of tamoxifen sensitivity in ER-positive MCF-7 cells, mediated, at least in part, through regulation of ER-α expression. Low expression of SIAH2 may be one of the mechanisms that contribute to tamoxifen resistance in human breast cancer.

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High-density array analysis of DNA methylation in Tamoxifen-resistant breast cancer cell lines

Cited by 26 publications

References 23 publications

DNA methylation in breast cancers: Differences based on estrogen receptor status and recurrence

DNA methylation in breast cancers: Differences based on estrogen receptor status and recurrence

Altered DNA methyltransferases promoter methylation and mRNA expression are associated with tamoxifen response in breast tumors

Seven In Absentia Homolog 2 (SIAH2) downregulation is associated with tamoxifen resistance in MCF-7 breast cancer cells

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