Abstract
BackgroundDNA methyltransferase 1 (DNMT1) plays a critical role in breast cancer progression. However, the epigenetic mechanism regulating DNMT1 expression remains largely unknown.MethodsEpigenetic regulation of DNMT1 was assessed in 85 invasive ductal carcinomas from BRCA1 mutation carriers. Association between clinicopathological features and DNMT1 promoter methylation was determined using Fisher’s exact test. Univariate analysis of survival was performed using the Kaplan-Meier method. Multivariate Cox regression analysis was performed to identify the independent prognostic factors for overall survival.ResultsHypermethylated E2F transcription factor 1 (E2F1) motif is a key regulatory element for the DNMT1 gene in BRCA1-mutated breast cancer. Mechanistically, the abnormal E2F1 motif methylation-mediated loss of active histone H3 lysine 9 acetylation (H3K9ac) and transcription factor E2F1 enrichment synergistically inhibited the transcription of DNMT1. Clinicopathological data indicated that the hypermethylated E2F1 motif was associated with histological grade, lymph node, Ki67 and E-cadherin status; univariate survival and multivariate analyses demonstrated that lymph node metastasis was an independent and reliable prognostic factor for BRCA1-mutated breast cancer patients.ConclusionsOur findings imply that genetic (such as BRCA1 mutation) and epigenetic mechanisms (such as DNA methylation, histone modification, transcription factor binding) are jointly involved in the malignant progression of DNMT1-related breast cancer.
Highlights
DNA methyltransferase 1 (DNMT1) plays a critical role in breast cancer progression
Low DNMT1 transcript levels showed a significant inverse correlation with hypermethylated E2F transcription factor 1 (E2F1) motif in BRCA1-mutated breast cancer Real-time polymerase chain reaction (PCR) and immunohistochemical analysis showed that the levels of DNMT1 mRNA and protein were decreased in BRCA1-mutated breast cancer, compared to adjacent normal breast tissues (P < 0.05; Figure 2C and D), DNMT1 protein levels was further confirmed by western blotting [see Additional file 1]
We analyzed the correlation between DNMT1-positive cells or mRNA levels and the number of methylated sites within the E2F1 motif (+182) or DNMT1 core promoter region (−99 to +521) in BRCA1-mutated breast cancer and adjacent normal breast tissue (Figure 2Ei-Eiv)
Summary
DNA methyltransferase 1 (DNMT1) plays a critical role in breast cancer progression. The epigenetic mechanism regulating DNMT1 expression remains largely unknown. Breast cancer is the most prevalent malignancy, and is a leading cause of mortality in women worldwide [1]. Accumulating evidence indicates that hereditary factors and epigenetic events are implicated in the initiation and progression of breast cancer and resistance to endocrine therapies [2]. BRCA mutations are the only known cause of hereditary breast cancer [3], and DNA novel insight into the mechanisms involved in the regulation of DNMT1 expression
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