Estrogen receptor-α promoter methylation is a biomarker for outcome prediction of cisplatin resistance in triple-negative breast cancer

A number of previous studies have indicated the presence of a link between estrogen receptor-alpha (ER alpha) methylation and triple-negative breast cancer (TNBC). However, the association between ERa methylation and drug resistance during the treatment of TNBC remains unclear. Methylation-specific polymerase chain reaction was used to investigate the methylation of ER alpha in the genomic DNA of 35 patients with TNBC who were defined as cisplatin-based chemotherapy-resistant using chemosensitivity testing. Survival probabilities by covariates were assessed using Kaplan-Meier estimator survival analysis and Cox's proportional hazards models, adjusting for age, menopausal status, tumor size, lymph node metastasis and ER alpha promoter DNA methylation. Of the 35 patients with TNBC analyzed, 8 exhibited ER alpha promoter DNA methylation. Cisplatin resistance was confirmed to be overwhelmingly associated with ER alpha methylation by univariate and multivariate analysis. Even in a limited analysis in patients with ER alpha methylation, the results generated from methylated tumor tissue and unmethylated tumor tissue revealed that expression of breast cancer type 1/2 susceptibility proteins was increased in ER alpha-methylated breast tumor tissue compared with in unmethylated tissue. The ER alpha methylation group tended to have significantly shorter progression-free (P=0.010) and overall (P=0.023) survival times compared with those in the unmethylated group. Similarly, shorter progression-free (P=0.024) and overall (P=0.018) survival times were observed in the cisplatin-resistant group compared with the cisplatin-non-resistant group. ER alpha methylation predicts a poor clinical outcome for patients with TNBC. The results of the present study indicated that ER alpha methylation may be a candidate surrogate biomarker for outcome prediction and cisplatin resistance in TNBC. Further investigation is required to identify potential biomarkers in a larger cohort in a prospective study.