Abstract
BackgroundWe assessed the expression of methylation-related proteins 5-meC, DNMT1, and ISL-1 in breast cancer and evaluated their relationship to clinicopathological factors.MethodsImmunohistochemical staining for ER, PR, HER-2, Ki-67, 5-meC, DNMT1, and ISL-1 were performed on 348 breast cancer samples in tissue microarray. Samples were subgrouped into luminal A, luminal B, HER-2, or triple-negative breast cancer (TNBC) according to immunohistochemical staining for ER, PR, HER-2, and Ki-67. The tumor stroma was histologically subtyped into desmoplastic, sclerotic, normal-like, or inflammatory type.ResultsTumor expression of DNMT1 differed by molecular subtype: it was higher in TNBC and lower in luminal A (p < 0.001) samples. DNMT1 expression was also related to higher histologic grade, ER negativity, PR negativity, and higher Ki-67 LI (p < 0.001). In western blot, protein expressions of DNMT1 and ISL-1 were higher in TNBC and relatively lower in the remaining subtypes. High tumor expression of DNMT1 was associated with shorter OS in univariate analysis (p = 0.041). DNMT1 and 5-meC were differentially expressed by stromal phenotype: 5-meC was higher in normal-like type and lower in sclerotic type (p = 0.049); DNMT1 was higher in inflammatory and lower in sclerotic type (p < 0.001).ConclusionsTumor expression of DNMT1 in breast cancer differed by molecular subtype and stromal histological type. DNMT1 was highly expressed in TNBC and in breast cancer with inflammatory stromal type.
Highlights
We assessed the expression of methylation-related proteins 5-meC, DNMT1, and ISL-1 in breast cancer and evaluated their relationship to clinicopathological factors
Expression of epigenetic methylation‐related proteins in breast cancer The epigenetic methylation-related proteins 5-meC and DNMT1 were expressed in both malignant cells and stromal cells, and ISL-1 was expressed only in the malignant cells
Expression analysis of epigenetic methylation-related proteins according to the molecular subtypes revealed that the expression of DNMT1 in malignant cells differs by molecular subtype (p < 0.001): it was higher in triple-negative breast cancer (TNBC) and lower in luminal A (Table 3 and Fig. 1)
Summary
We assessed the expression of methylation-related proteins 5-meC, DNMT1, and ISL-1 in breast cancer and evaluated their relationship to clinicopathological factors. One of the most important features differentiating cancer cells from normal cells is insensitivity to growth inhibitory signals. This insensitivity mostly occurs through the inhibition of tumor suppressor genes [1] by DNA hypermethylation. DNA hypermethylation is initiated by DNA methyltransferases (DNMTs) [2]. Genes for the DNMTs identified to date are DNMT1, DNMT2, DNMT3A, and DNMT3B. DNMT1 is a key maintenance methyltransferase and is the most common methyltransferase in humans. Molecules associated with DNMT1 are 5-methylcytosine (5-MeC) and insulin gene enhancer
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