Hypermethylated 14-3-3-σ and ESR1 gene promoters in serum as candidate biomarkers for the diagnosis and treatment efficacy of breast cancer metastasis

Abstract

BackgroundNumerous hypermethylated genes have been reported in breast cancer, and the silencing of these genes plays an important role in carcinogenesis, tumor progression and diagnosis. These hypermethylated promoters are very rarely found in normal breast. It has been suggested that aberrant hypermethylation may be useful as a biomarker, with implications for breast cancer etiology, diagnosis, and management. The relationship between primary neoplasm and metastasis remains largely unknown. There has been no comprehensive comparative study on the clinical usefulness of tumor-associated methylated DNA biomarkers in primary breast carcinoma and metastatic breast carcinoma. The objective of the present study was to investigate the association between clinical extension of breast cancer and methylation status of Estrogen Receptor1 (ESR1) and Stratifin (14-3-3-σ) gene promoters in disease-free and metastatic breast cancer patients.MethodsWe studied two cohorts of patients: 77 patients treated for breast cancer with no signs of disease, and 34 patients with metastatic breast cancer. DNA was obtained from serum samples, and promoter methylation status was determined by using DNA bisulfite modification and quantitative methylation-specific PCR.ResultsSerum levels of methylated gene promoter 14-3-3-σ significantly differed between Control and Metastatic Breast Cancer groups (P < 0.001), and between Disease-Free and Metastatic Breast Cancer groups (P < 0.001). The ratio of the 14-3-3-σ level before the first chemotherapy cycle to the level just before administration of the second chemotherapy cycle was defined as the Biomarker Response Ratio [BRR]. We calculated BRR values for the "continuous decline" and "rise-and-fall" groups. Subsequent ROC analysis showed a sensitivity of 75% (95% CI: 47.6 - 86.7) and a specificity of 66.7% (95% CI: 41.0 - 86.7) to discriminate between the groups for a cut-off level of BRR = 2.39. The area under the ROC curve (Z = 0.804 ± 0.074) indicates that this test is a good approach to post-treatment prognosis.ConclusionsThe relationship of 14-3-3-σ with breast cancer metastasis and progression found in this study suggests a possible application of 14-3-3-σ as a biomarker to screen for metastasis and to follow up patients treated for metastatic breast cancer, monitoring their disease status and treatment response.

DNA methylation-based biomarkers in serum of patients with breast cancer

“…The 14-3-3 proteins are a family of widely expressed regulatory molecules in signal transduction, cell cycle control (G2 checkpoint) and apoptotic cell death. 14-3-3-sigma sequesters the cdc2-cyclin B1 complex in the cytoplasm, resulting in G2 arrest [19,114]. It is one of the most frequent and early methylated genes in the progression from normal to atypical hyperplasia, to DCIS and finally to invasive carcinoma.…”

The mitogen-activated protein kinase phosphatase-1 (MKP-1) gene is a potential methylation biomarker for malignancy of breast cancer

“…The CpG methylation signatures have been reported to be the potential diagnostic, prognostic, and predictive tools for breast cancer (Jovanovic et al, 2010;Parrella, 2010). The methylation analysis also improves early breast cancer detection (Caldeira et al, 2006;Noetzel et al, 2008;Henneges et al, 2009;Seniski et al, 2009;Veeck et al, 2009;Wu et al, 2010;Zurita et al, 2010;Suijkerbuijk et al, 2011). However, the relationship between MKP-1 gene expression and methylation in breast cancer remains unclear.…”

CNAPS in Therapy Monitoring

“…In a genome-scale screen, IFFO1 methylation was identified as a meaningful marker for ovarian cancer that showed, in a subsequent validation study, similar post-resection kinetics to CA 125 [162]. Further small follow-up studies identified concordances of serum methylation markers and disease status for RASSF1A and ovarian cancer [163], for ESR1 and 14-3-3-sigma and breast cancer [164], and for p16INK4a and colorectal cancer [165]. Presurgery RUNX3 methylation was predictive for the relapse of colorectal cancer [166] and serum RASSF1A methylation status one year after breast cancer surgery indicated the long-term outcome [167].…”