Abstract
BackgroundAberrant hypermethylation of gene promoter regions is a primary mechanism by which tumor suppressor genes become inactivated in breast cancer. Epigenetic inactivation of the protein tyrosine phosphatase receptor-type O gene (PTPRO) has been described in several types of cancer.ResultsWe screened primary breast cancer tissues for PTPRO promoter hypermethylation and assessed potential associations with pathological features and patient outcome. We also evaluated its potential as a breast cancer biomarker. PTPRO methylation was observed in 53 of 98 (54%) breast cancer tissues but not in adjacent normal tissue. Among matched peripheral blood samples from breast cancer patients, 33 of 98 (34%) exhibited methylated PTPRO in plasma. In contrast, no methylated PTPRO was observed in normal peripheral blood from 30 healthy individuals. PTPRO methylation was positively associated with lymph node involvement (P = 0.014), poorly differentiated histology (P = 0.037), depth of invasion (P = 0.004), and HER2 amplification (P = 0.001). Multivariate analysis indicated that aberrant PTPRO methylation could serve as an independent predictor for overall survival hazard ratio (HR): 2.7; 95% CI: 1.1-6.2; P = 0.023), especially for patients with HER2-positive (hazard ratio (HR): 7.5; 95% CI: 1.8-31.3; P = 0.006), but not in ER + and PR + subpopulation. In addition, demethylation induced by 5-azacytidine led to gene reactivation in PTPRO-methylated and -silenced breast cancer cell lines.ConclusionsHere, we report that tumor PTPRO methylation is a strong prognostic factor in breast cancer. Methylation of PTPRO silences its expression and plays an important role in breast carcinogenesis. The data we present here may provide insight into the development of novel therapies for breast cancer treatment. Additionally, detection of PTPRO methylation in peripheral blood of breast cancer patients may provide a noninvasive means to diagnose and monitor the disease.
Highlights
Aberrant hypermethylation of gene promoter regions is a primary mechanism by which tumor suppressor genes become inactivated in breast cancer
We examined the methylation status of phosphatase receptor-type O gene (PTPRO) in primary breast tumors and matched peripheral blood samples and determined if promoter methylation was associated with decreased gene expression in breast cancer cell lines
Frequent methylation of PTPRO in primary tumors and peripheral blood samples Methylation of the PTPRO promoter has been demonstrated in different tumor types, including breast cancer [7,8,10]
Summary
Aberrant hypermethylation of gene promoter regions is a primary mechanism by which tumor suppressor genes become inactivated in breast cancer. Promoter hypermethylation is a type of epigenetic alteration associated with gene silencing. Many tumor suppressor genes are inactivated in this way. Hypermethylation of key tumor suppressors is a key contributor to breast tumorigenesis and acts in concert with genetic alterations to drive disease progression [4]. Epigenetic modifications of tumor DNA may have prognostic significance for breast cancer patients and provide targets for treatment because they are potentially reversible. Epigenetic changes may serve as markers for early detection of the disease. As an example, screening for RASSF1A hypermethylation in serum has been proposed as a form of surveillance to detect early stage breast cancer [5]
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