Age is a significant risk factor for breast cancer and luminal epithelial cells (LEps) are a key cell lineage implicated in age-related luminal breast cancers. The aging process is characterized by alterations to the epigenome. However, the extent of age-associated DNA methylation alterations in LEps and its functional consequences have remained unclear. We report here that aging leads to distinct methylation changes in LEps that may increase susceptibility to breast cancer. Regulatory elements display consistent methylation changes at lineage-specific TF binding sites consistent with loss of lineage fidelity. CpG islands and transposable elements (TEs) showed increased methylation disorder with stochastic methylation gain and loss respectively that were also detected in luminal breast cancer. Each of these classes of methylation changes impact the regulation of genes associated with luminal breast cancer. Altogether, our results indicate that aging leads to DNA methylation changes that could determine breast cancer susceptibility.

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衰老导致 DNA 甲基化改变与乳腺管腔上皮细胞中谱系保真度的丧失和乳腺癌相关

年龄是乳腺癌的重要危险因素，管腔上皮细胞 (LEps) 是与年龄相关的管腔乳腺癌相关的关键细胞谱系。衰老过程的特征在于表观基因组的改变。然而，LEps 中与年龄相关的 DNA 甲基化改变的程度及其功能后果仍不清楚。我们在此报告，衰老会导致 LEps 中明显的甲基化变化，这可能会增加对乳腺癌的易感性。调控元件在谱系特异性 TF 结合位点显示出一致的甲基化变化，与谱系保真度的丧失一致。CpG 岛和转座因子 (TEs) 显示甲基化障碍增加，并分别在管腔乳腺癌中检测到随机甲基化增益和缺失。这些类型的甲基化变化中的每一种都会影响与管腔乳腺癌相关的基因的调节。总之，我们的研究结果表明，衰老会导致 DNA 甲基化变化，从而决定乳腺癌的易感性。