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ESR1 gene promoter region methylation in free circulating DNA and its correlation with estrogen receptor protein expression in tumor tissue in breast cancer patients

Joaquina Martínez-Galán1*, Blanca Torres-Torres2, María Isabel Núñez3, Jesús López-Peñalver2, Rosario Del Moral4, José Mariano Ruiz De Almodóvar2, Salomón Menjón5, Ángel Concha6, Clara Chamorro6, Sandra Ríos3 and Juan Ramón Delgado1

Author Affiliations

1 Department of Medical Oncology, Hospital Universitario Virgen de las Nieves, University of Granada, Avenida de las Fuerzas Armadas s/n, 18011 Granada, Spain

2 Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain

3 Departamento de Radiología y Medicina Física, Facultad de Medicina de Granada, Granada, Spain

4 Servicio de Oncología Radioterápica, Hospital Universitario Virgen de las Nieves, Granada, Spain

5 Servicio de Ginecología, Hospital Universitario Virgen de las Nieves, Granada, Spain

6 Servicio de Anatomía Patológica, Hospital Universitario Virgen de las Nieves, Granada, Spain

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BMC Cancer 2014, 14:59  doi:10.1186/1471-2407-14-59

Published: 4 February 2014



Tumor expression of estrogen receptor (ER) is an important marker of prognosis, and is predictive of response to endocrine therapy in breast cancer. Several studies have observed that epigenetic events, such methylation of cytosines and deacetylation of histones, are involved in the complex mechanisms that regulate promoter transcription. However, the exact interplay of these factors in transcription activity is not well understood. In this study, we explored the relationship between ER expression status in tumor tissue samples and the methylation of the 5′ CpG promoter region of the estrogen receptor gene (ESR1) isolated from free circulating DNA (fcDNA) in plasma samples from breast cancer patients.


Patients (n = 110) with non-metastatic breast cancer had analyses performed of ER expression (luminal phenotype in tumor tissue, by immunohistochemistry method), and the ESR1-DNA methylation status (fcDNA in plasma, by quantitative methylation specific PCR technique).


Our results showed a significant association between presence of methylated ESR1 in patients with breast cancer and ER negative status in the tumor tissue (p = 0.0179). There was a trend towards a higher probability of ESR1-methylation in those phenotypes with poor prognosis i.e. 80% of triple negative patients, 60% of HER2 patients, compared to 28% and 5.9% of patients with better prognosis such as luminal A and luminal B, respectively.


Silencing, by methylation, of the promoter region of the ESR1 affects the expression of the estrogen receptor protein in tumors of breast cancer patients; high methylation of ESR1-DNA is associated with estrogen receptor negative status which, in turn, may be implicated in the patient’s resistance to hormonal treatment in breast cancer. As such, epigenetic markers in plasma may be of interest as new targets for anticancer therapy, especially with respect to endocrine treatment.

Breast cancer; Methylation; Luminal phenotypes