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Updated: Dec 14, 2025
Methyl-binding DNA capture Sequencing for Patient Tissues
Published on: October 31, 2016
Candidate methylation sites associated with endocrine therapy resistance in ER+/HER2- breast cancer
Maryam Soleimani Dodaran1,2, Simone Borgoni3,4, Emre Sofyalı3,4
1Bioinformatics Laboratory, Department of Clinical Epidemiology, Biostatistics, and Bioinformatics, Amsterdam Public Health research institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, AZ, 1105, The Netherlands.
Background:
Estrogen receptor (ER) positive breast cancer is often effectively treated with drugs that inhibit ER signaling, i.e., tamoxifen (TAM) and aromatase inhibitors (AIs). However, 30% of ER+ breast cancer patients develop resistance to therapy leading to tumour recurrence. Changes in the methylation profile have been implicated as one of the mechanisms through which therapy resistance develops. Therefore, we aimed to identify methylation loci associated with endocrine therapy resistance.
Methods:
We used genome-wide DNA methylation profiles of primary ER+/HER2- tumours from The Cancer Genome Atlas in combination with curated data on survival and treatment to predict development of endocrine resistance. Association of individual DNA methylation markers with survival was assessed using Cox proportional hazards models in a cohort of ER+/HER2- tumours (N = 552) and two sub-cohorts corresponding to the endocrine treatment (AI or TAM) that patients received (N = 210 and N = 172, respectively). We also identified multivariable methylation signatures associated with survival using Cox proportional hazards models with elastic net regularization. Individual markers and multivariable signatures were compared with DNA methylation profiles generated in a time course experiment using the T47D ER+ breast cancer cell line treated with tamoxifen or deprived from estrogen.
Results:
We identified 134, 5 and 1 CpGs for which DNA methylation is significantly associated with survival in the ER+/HER2-, TAM and AI cohorts respectively. Multi-locus signatures consisted of 203, 36 and 178 CpGs and showed a large overlap with the corresponding single-locus signatures. The methylation signatures were associated with survival independently of tumour stage, age, AI treatment, and luminal status. The single-locus signature for the TAM cohort was conserved among the loci that were differentially methylated in endocrine-resistant T47D cells. Similarly, multi-locus signatures for the ER+/HER2- and AI cohorts were conserved in endocrine-resistant T47D cells. Also at the gene set level, several sets related to endocrine therapy and resistance were enriched in both survival and T47D signatures.
Conclusions:
We identified individual and multivariable DNA methylation markers associated with therapy resistance independently of luminal status. Our results suggest that these markers identified from primary tumours prior to endocrine treatment are associated with development of endocrine resistance.
Insights
DNA methylation markers can predict endocrine therapy resistance in estrogen receptor-positive breast cancer. These markers, identified before treatment, are linked to tumor recurrence and offer potential for personalized treatment strategies.
Area of Science:
- Oncology
- Genetics
- Epigenetics
Background:
- Estrogen receptor (ER) positive breast cancer is often treated with endocrine therapies like tamoxifen (TAM) and aromatase inhibitors (AIs).
- A significant portion of patients (30%) develop resistance to these therapies, leading to tumor recurrence.
- Epigenetic alterations, specifically DNA methylation changes, are implicated in the development of endocrine therapy resistance.
Purpose of the Study:
- To identify specific DNA methylation loci associated with endocrine therapy resistance in ER+ breast cancer.
- To investigate the relationship between DNA methylation profiles and patient survival following endocrine treatment.
Main Methods:
- Utilized genome-wide DNA methylation profiles from The Cancer Genome Atlas (TCGA) for ER+/HER2- tumors.
- Employed Cox proportional hazards models to assess the association of individual DNA methylation markers with survival in distinct patient cohorts (overall, TAM-treated, AI-treated).
- Identified multivariable methylation signatures using elastic net regularization and compared findings with methylation profiles from tamoxifen-treated T47D ER+ breast cancer cells.
Main Results:
- Identified 134, 5, and 1 CpG sites significantly associated with survival in the ER+/HER2-, TAM, and AI cohorts, respectively.
- Developed multi-locus methylation signatures (203, 36, and 178 CpGs) that overlapped with single-locus findings and were independent of tumor stage, age, and luminal status.
- Demonstrated conservation of methylation signatures in endocrine-resistant T47D cells, with enrichment of gene sets related to endocrine therapy and resistance.
Conclusions:
- Identified individual and multivariable DNA methylation markers associated with endocrine therapy resistance, independent of luminal status.
- These methylation markers, detected in primary tumors before treatment, are predictive of endocrine resistance development.
- Suggests potential for using these epigenetic markers to guide personalized treatment strategies for ER+ breast cancer patients.
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