Hormone Therapy Use and Breast Tissue DNA Methylation: Analysis of Epigenome Wide Data from the Normal Breast Study
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PROVIDER: PRJNA422860 | ENA |
REPOSITORIES: ENA
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Project description:Genome wide DNA methylation profiling of fresh frozen, histologically normal-appearing breast tissue from the Normal Breast Study (NBS). The Illumina HumanMethylation450 BeadChip was used to obtain DNA methylation profiles for 90 samples, including “current”, “former” and never users of HRT.
2017-12-19 | GSE108213 | GEO
Project description:Hormone therapy (HT) is associated with increased risk of breast cancer, strongly dependent on type, duration, and recency of use. HT use could affect cancer risk by changing breast tissue transcriptional programs. We hypothesize that these changes are preceded by changes in DNA methylation. To explore this hypothesis we used histologically normal-appearing breast tissue from the Normal Breast Study (NBS). DNA methylation β-values were obtained using the Illumina HumanMethylation 450 BeadChips for 90 samples including all NBS-participants who used HT within 5 y before surgery. Data were analyzed using the reference-free cell mixture method. Cancer Genome Atlas (TCGA) mRNA-Seq data were used to assess correlation between DNA methylation and gene expression. We identified 527 CpG sites in 403 genes that were associated with ever using HT at genome wide significance (FDR q < 0.05), of these, 68 sites were also significantly associated with duration of use or recency of use. Twelve sites reached significance in all analyses one of which was cg01382688 in ARHGEF4 (p < 1.2x10-7). Mutations in ARHGEF4 have been reported in breast tumors, but this is the first report of possible breast cancer-related DNA methylation changes. In addition, 22 genes included more than one significant CpG site and a majority of these sites were significantly correlated with gene expression. Although based on small numbers, these findings support the hypothesis that HT is associated with epigenetic alterations in breast tissue, and identifies genes with altered DNA methylation states which could be linked to breast cancer development.
| S-EPMC6557608 | biostudies-literature
Project description:Core needle biopsy (Cx) primary cancer specimens were collected at Okayama University Hospital in Japan from hormone receptor positive /HER2 negative patients that subsequently received two weeks of neoadjuvant hormone therapy. Thirty clinical TNM stage I and II women were enrolled in this study. The study was approved by the Institutional Review Board and all patients signed informed consent forms. Patients received preoperative hormone therapy daily for two weeks before surgery. Premenopausal patients received tamoxifen (40 mg) and postmenopausal patients received letrozole (2.5 mg). All patients underwent a mastectomy or breast-conserving surgery. Surgical samples after treatment were also collected. Hormone and HER2 receptor statuses were determined in the diagnostic Cx specimens before hormone therapy. Cases with ≥1% positive nuclear staining for estrogen receptors (ER) or progesterone receptors (PgR) with IHC were considered hormone receptor-positive. Cases with either 0 or 1 positive IHC staining for HER2 or with an HER2 gene copy number < 2.0 by fluorescent in situ hybridization (FISH) analysis were considered HER2−. Specimens for gene expression analysis were collected into RNA and later stored at -80°C. Gene expression profiling was performed using Affymetrix U133A gene chips. Expression data were normalized using the MAS5 algorithm, mean centered to 600, and log2 transformed before further analysis.
2017-04-19 | GSE80077 | GEO
Project description:Epigenome analysis of normal and breast cancer(BC) samples
| PRJNA993607 | ENA
Project description:Here we investigate the impact of epigenetic therapy with Decitabine in endocrine-resistant ER+ breast cancer by using patient-derived xenograft (PDX) models. Decitabine treatment restrained tumour growth, inhibited cell proliferation and resulted in significant loss of DNA methylation, particularly at enhancers and repetitive elements. Systematic integration of matched in situ Hi-C / PCHi-C, EPIC, RNA-seq and ChIP–seq datasets revealed widespread differences in epigenome regulation and enhancer-promoter communication with Decitabine. We find that loss of DNA methylation with Decitabine strongly affects the open (A) and closed (B) compartment structure and TAD boundary insulation. Our study identified and focused on key DNA methylation-dependent, enhancer ER binding sites that are activated in Decitabine-treated PDX tumours, enabling direct interactions between promoters and multiple distal enhancers, inducing expression of ER target genes and pathways. Overall, we demonstrate that epigenetic therapy inhibits tumour progression through to rewiring of ER-mediated 3D chromatin interactions and transcriptome programs. Our findings suggest that targeting the 3D epigenome with epigenetic therapies represents a promising strategy for anti-cancer treatment in ER+ endocrine resistant breast cancer patients.
2023-07-24 | GSE237768 | GEO
Project description:Male breast cancer (MBC) is rare and poorly characterized. Like the female counterpart, most MBCs are hormonally driven, but resistance to hormonal treatment is common. We use transcriptomics to reveal gender-selective and genomic location-specific hormone receptor actions, which associated with survival in MBC patients.
2018-02-02 | GSE104730 | GEO
Project description:Here we investigate the impact of epigenetic therapy with Decitabine in endocrine-resistant ER+ breast cancer by using patient-derived xenograft (PDX) models. Decitabine treatment restrained tumour growth, inhibited cell proliferation and resulted in significant loss of DNA methylation, particularly at enhancers and repetitive elements. Systematic integration of matched in situ Hi-C / PCHi-C, EPIC, RNA-seq and ChIP–seq datasets revealed widespread differences in epigenome regulation and enhancer-promoter communication with Decitabine. We find that loss of DNA methylation with Decitabine strongly affects the open (A) and closed (B) compartment structure and TAD boundary insulation. Our study identified and focused on key DNA methylation-dependent, enhancer ER binding sites that are activated in Decitabine-treated PDX tumours, enabling direct interactions between promoters and multiple distal enhancers, inducing expression of ER target genes and pathways. Overall, we demonstrate that epigenetic therapy inhibits tumour progression through to rewiring of ER-mediated 3D chromatin interactions and transcriptome programs. Our findings suggest that targeting the 3D epigenome with epigenetic therapies represents a promising strategy for anti-cancer treatment in ER+ endocrine resistant breast cancer patients.
2023-07-24 | GSE237769 | GEO
Project description:<p><strong>INTRODUCTION:</strong> Postmenopausal hormone use is linked to several health outcomes and the risk associated with some may differ depending on whether estrogen is used alone or in combination with progestin.</p><p><strong>OBJECTIVE:</strong> Metabolomic analyses of postmenopausal hormone use and differences between hormone regimes was carried out to identify metabolites associated with each type of hormone treatment.</p><p><strong>METHODS:</strong> Untargeted metabolomics analysis was carried out on serum from 1,336 women enrolled in the Cancer Prevention II Nutrition Cohort. Levels of 781 named metabolites were compared between 667 nonusers with 332 estrogen-only and with 337 estrogen plus progestin users using linear regression. Metabolite levels were also compared between estrogen-only and estrogen plus progestin users.</p><p><strong>RESULTS:</strong> Compared to nonusers, 276 metabolites were statistically significantly (P<6.40 x 10-5) associated with estrogen-only use and 222 were associated with estrogen plus progestin use. The metabolites associated with both types of hormones included numerous lipids, acyl carnitines, and amino acids as well as the thyroid hormone thyroxine and the oncometabolite fumarate. The 65 metabolites that differed significantly between estrogen-only and estrogen plus progestin users included 19 steroids and 12 lipids that contained the bioactive fatty acid arachidonic acid.</p><p><strong>CONCLUSIONS:</strong> These findings suggest that postmenopausal hormone use influences metabolic pathways linked to a variety of cellular processes, including the regulation of metabolism and stress responses, energy production, and inflammation. The differential association of numerous lipids that could influence cellular signaling suggests that differences in signal transduction may contribute to the disparate risks for some diseases between estrogen-only and estrogen plus progestin users.</p>
2019-06-02 | MTBLS136 | MetaboLights
Project description:Despite known age-related DNA methylation (aDNAm) changes in breast tumors, little is known about aDNAm in normal breast tissues. Breast tissues from a cross-sectional study of 121 cancer-free women, were assayed for genome-wide DNA methylation. mRNA expression was assayed by microarray technology. Analysis of covariance was used to identify aDNAm’s. Altered methylation was correlated with expression of the corresponding gene and with DNA methyltransferase protein DNMT3A, assayed by immunohistochemistry. Publically-available TCGA data were used for replication. 1,214 aDNAm’s were identified; 97% with increased methylation, and all on autosomes. Sites with increased methylation were predominantly in CpG lslands and non-enhancers. aDNAm’s with decreased methylation were generally located in intergenic regions, non-CpG Islands, and enhancers. Of the aDNAm’s identified, 650 are known to be involved in cancer, including ESR1 and beta-estradiol responsive genes. Expression of DNMT3A was positively associated with age. Two aDNAm’s showed significant associations with DNMT3A expression; KRR1 (OR 6.57, 95% CI: 2.51-17.23) and DHRS12 (OR 6.08, 95% CI: 2.33-15.86). A subset of aDNAm’s co-localized within vulnerable regions for somatic mutations in breast cancer. Expression of C19orf48 was inversely and significantly correlated with its methylation level. In the TCGA dataset, 84% and 64% of the previously identified aDNAm’s were correlated with age in both normal-adjacent and tumor breast tissues, with differential associations by histological subtype. Given the similarity of findings in the breast tissues of healthy women and breast tumors, and the effects on gene expression, aDNAm’s may be one pathway for increased breast cancer risk with age.
2017-07-28 | GSE101961 | GEO
Project description:Hormone treatment of ER+ breast cancer cell lines
| PRJNA807655 | ENA