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Candidate ERalpha targets for DNA methylation-mediated gene silencing

ABSTRACT: DNA methylation of specific CpG sites associates with estrogen receptor α (ERα)-positive status in human breast cancer. Therefore, ERα may regulate gene expression in part via DNA methylation. This hypothesis was tested in a panel of antihormone-resistant T47D and MCF-7 cells with varying levels of ERα expression/activity that were derived by long-term fulvestrant treatment and by estrogen deprivation. Using Agilent’s Whole Human Genome 4x44K v2 gene expression microarrays, the intersection of ERα inversely-related genes and genes induced by the DNA methyltransferase-inhibitor decitabine were identified and revealed 39 candidate ERα DNA methylation targets. Enrichment analysis indicated over-representation of ERα-binding sites, basal-up/luminal-down markers, cancer stem cell genes, epithelial-mesenchymal transition (EMT) genes, inflammatory genes and tumor suppressors. Kaplan-Meier survival curve and Cox proportional hazard regression analyses indicated these candidate targets predicted poor distant metastasis-free survival among 2,116 breast cancer patients. The basal and EMT genes LCN2 and IFI27 showed the greatest inverse relationship with ERα expression/activity and contain ERα-binding sites, therefore they were selected for validation. LCN2 and IFI27 CpG methylation levels, quantitated by pyrosequencing, were inversely related to ERα expression/activity in wild-type and antihormone-resistant ERα-negative T47D cells, in ERα-negative T47D cells infected with lentiviral ERα, and in a panel of 11 breast cancer cell lines. Implications: ERα directs DNA methylation-mediated silencing of specific genes, such as basal markers, and thereby may in part program breast cancers as the prognostically more favorable luminal subtype. Thus, genes that can be methylated in an ERα-dependent manner may serve as predictive biomarkers in breast cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE85536 | GEO | 2017/02/05

SECONDARY ACCESSION(S): PRJNA338758

REPOSITORIES: GEO

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Project description:Introduction: Five different molecular subtypes of breast cancer have been identified through gene expression profiling. Each subtype has a characteristic expression pattern suggested to partly depend on cellular origin. We aimed to investigate whether the molecular subtypes also display distinct methylation profiles. Methods: We analysed methylation status of 807 cancer-related genes in 189 fresh frozen primary breast tumours and four normal breast tissue samples using an array-based methylation assay. Results: Unsupervised analysis revealed three groups of breast cancer with characteristic methylation patterns. The three groups were associated with the luminal A, luminal B and basal-like molecular subtypes of breast cancer, respectively, whereas cancers of the HER2-enriched and normal-like subtypes were distributed among the three groups. The methylation frequencies were significantly different between subtypes, with luminal B and basal-like tumours being most and least frequently methylated, respectively. Moreover, targets of the polycomb repressor complex in breast cancer and embryonic stem cells were more methylated in luminal B tumours than in other tumours. BRCA2-mutated tumours had a particularly high degree of methylation. Finally, by utilizing gene expression data, we observed that a large fraction of genes reported as having subtype-specific expression patterns might be regulated through methylation. Conclusions: We have found that breast cancers of the basal-like, luminal A and luminal B molecular subtypes harbour specific methylation profiles. Our results suggest that methylation may play an important role in the development of breast cancers. DNA methylation profiling of breast cancer samples and normal breast tissue samples. The Illumina GoldenGate Methylation Cancer Panel I was used to obtain DNA methylation profiles across approximately 1500 CpGs. Samples included 189 breast cancer samples and 4 normal breast tissue samples. Bisulphite converted DNA from the samples were hybridised to the Illumina GoldenGate Methylation Cancer Panel I

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Candidate ERalpha targets for DNA methylation-mediated gene silencing

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