Expression of DNA methylation-related proteins in metastatic breast cancer

Abstract

We aimed to investigate the expression of methylation-related proteins (5-meC and DNMT1) in the metastatic breast cancers of variable sites and its association with clinicopathologic factors. A total of 126 metastatic breast cancers (31 bone metastases, 36 brain metastases, 11 liver metastases, 48 lung metastases) were made into tissue microarray and immunohistochemical staining of ER, PR, HER-2, Ki-67, 5-meC, and DNMT1 were performed. Molecular classification was made on the basis of immunohistochemical staining result of ER, PR, HER-2, Ki-67; luminal A, luminal B, HER-2, triple negative breast cancer (TNBC). Methylation-related proteins were differentially expressed based on the metastatic sites. Tumoral and stromal 5-meC showed the lowest expression in the bone metastasis (P < 0.001), tumoral DNMT1 showed the least expression in bone metastasis and the highest expression in the brain metastasis (P < 0.001). Expression of DNMT1 was correlated with ER negativity (P = 0.004), PR negativity (P = 0.011), HER-2 positivity (P = 0.016), higher Ki-67 labeling indices (P = 0.016), and non-luminal A type (P = 0.017). DNMT1 positivity was associated with shorter overall survival in bone metastasis (P = 0.017) and lung metastasis (P = 0.028) by univariate analysis. In conclusion, methylation-related proteins differentially expressed according to the metastatic sites in metastatic breast cancer. Tumoral and stromal 5-meC showed the lowest expression in the bone metastasis. Tumoral DNMT1 expression was low in bone metastasis and highest in brain metastasis.

ABCC9, NKAPL, and TMEM132C are potential diagnostic and prognostic markers in triple‐negative breast cancer

“…Genomic analysis of somatic mutations has provided extensive data, but little tumor mutations have been identified to be characteristic for TNBC, while gene expression profiling analysis has offered several successful approaches to classify TNBC, including keratin 5, EGFR, and laminin (Denkert, Liedtke, Tutt, & von Minckwitz, 2017). Current efforts have focused on DNA methylation signatures as potential molecular biomarkers of breast cancer (Cha, Jung, & Koo, 2017). Several aberrant methylation events in TNBC have been reported and identified as specific biomarkers that have significant diagnostic and prognostic potential (Bustos et al, 2017; Coyle et al, 2018; Mathe et al, 2016).…”

Epigenetic control of the vicious cycle

“…DNA methylation is maintained by DNA methyltransferases (DNMTs), which are encoded by genes including DNMT1, DNMT2, DNMT3A, and DNMT3B. To determine if changes in the levels of DNMTs contribute to increased promoter methylation of bone metastatic breast cancer cells, a study investigated DNMT1 expression in 31 cases of bone metastatic invasive ductal carcinoma and found that DNMT1 is expressed in tumor cells but not stromal cells, and DNMT1 is lowest in bone metastatic tumor cells compared to brain metastases [7] . However, DNMT1 positivity is associated with shorter overall survival for patients with bone metastases.…”

“…NCT00359606 is a phase I trial using intravenous 5-fluoro-2′-deoxycytidine (5-fluoro-2-deoxycytidine) (FdCyd), a DNA methyltransferase inhibitor, paired with the cytidine deaminase inhibitor tetrahydrouridine (THU). Given previous findings highlighting the important role of DNA hypermethylation in metastasis and tumor progression [4] , [5] , [6] , [7] , [8] , [9] , [10] , investigators hypothesized that FdCyd would be more successful at treating advanced solid tumors, including metastatic breast cancer, than THU alone. However, recent studies highlight the role of DNA hypomethylation in elevated expression of oncogenes associated with bone metastasis [9] , [10] .…”

Novel mediators of breast cancer bone metastasis—insights from studies of gene-regulation and the global proteome

“…Despite this, alterations in DNA methylation have demonstrated utility as potential markers predictive of bone metastasis risk. Levels of promoter methylation are observed to be lower in breast cancer bone metastases than in brain metastases, and elevated levels of DNA-methyltransferase-I (DNMTI) are prognostic for shorter overall survival within bone metastasis (36). High-throughput profiling of global DNA-methylation patterns has identified panels of gene methylation which can be used to predict metastatic lethal progression within prostate cancer (37).…”