A robust breast cancer prevention strategy requires risk assessment biomarkers for early detection. We show that expression of ELF5 , a transcription factor critical for normal mammary development, is downregulated in mammary luminal epithelia with age. DNA methylation of the ELF5 promoter is negatively correlated with expression in an age-dependent manner. Both ELF5 methylation and gene expression were used to build biological clocks to estimate chronological ages of mammary epithelia. ELF5 clock-based estimates of biological age in luminal epithelia from average-risk women were within three years of chronological age. Biological ages of breast epithelia from BRCA1 or BRCA2 mutation carriers, who were high risk for developing breast cancer, suggested they were accelerated by two decades relative to chronological age. The ELF5 DNA methylation clock had better performance at predicting biological age in luminal epithelial cells as compared with two other epigenetic clocks based on whole tissues. We propose that the changes in ELF5 expression or ELF5 -proximal DNA methylation in luminal epithelia are emergent properties of at-risk breast tissue and constitute breast-specific biological clocks. Prevention Relevance: ELF5 expression or DNA methylation level at the ELF5 promoter region can be used as breast-specific biological clocks to identify women at higher than average risk of breast cancer.

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由 ELF5 表达和启动子甲基化组成的乳腺特异性分子钟可识别易患癌症的个体

一个强有力的乳腺癌预防策略需要风险评估生物标志物用于早期检测。我们显示 ELF5 的表达，一种对正常乳腺发育至关重要的转录因子，随着年龄的增长在乳腺管腔上皮细胞中下调。ELF5 启动子的 DNA 甲基化以年龄依赖性方式与表达呈负相关。ELF5 甲基化和基因表达都用于建立生物钟以估计乳腺上皮细胞的实际年龄。基于 ELF5 时钟的平均风险女性管腔上皮生物年龄估计在实际年龄的三年内。来自 BRCA1 或 BRCA2 突变携带者的乳腺上皮细胞的生物学年龄，他们是患乳腺癌的高风险，表明他们相对于实际年龄加速了二十年。与其他两个基于整个组织的表观遗传时钟相比，ELF5 DNA 甲基化时钟在预测管腔上皮细胞的生物学年龄方面具有更好的性能。我们提出 ELF5 表达或管腔上皮细胞中 ELF5 近端 DNA 甲基化的变化是处于危险中的乳腺组织的紧急特性，并构成乳腺特异性生物钟。预防相关性：ELF5 启动子区域的 ELF5 表达或 DNA 甲基化水平可用作乳房特异性生物钟，以识别乳腺癌风险高于平均水平的女性。我们提出 ELF5 表达或管腔上皮细胞中 ELF5 近端 DNA 甲基化的变化是处于危险中的乳腺组织的紧急特性，并构成乳腺特异性生物钟。预防相关性：ELF5 启动子区域的 ELF5 表达或 DNA 甲基化水平可用作乳房特异性生物钟，以识别乳腺癌风险高于平均水平的女性。我们提出 ELF5 表达或管腔上皮细胞中 ELF5 近端 DNA 甲基化的变化是处于危险中的乳腺组织的紧急特性，并构成乳腺特异性生物钟。预防相关性：ELF5 启动子区域的 ELF5 表达或 DNA 甲基化水平可用作乳房特异性生物钟，以识别乳腺癌风险高于平均水平的女性。