PO.CL01.19 · 临床研究
ELF5时钟：乳腺组织加速衰老和癌症易感性的预测标志物
The ELF5 clock: A predictive marker for accelerated breast tissue aging and cancer susceptibility
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
衰老是乳腺癌（BC）最重要的风险因素。它与转化性变化相关，尤其是管腔上皮细胞谱系保真度的显著丧失。这种丧失的特征是谱系特异性基因表达的下降以及获得EMT样和肌上皮样特征，同时伴有转录组和甲基化组变异性的增加。在携带BRCA1、BRCA2和PALB2致病突变的年轻女性中，这些衰老相关表型（包括管腔上皮细胞谱系保真度的丧失）加速出现。这些变化值得更密切的研究，因为管腔上皮细胞是与衰老最相关的BC亚型的可能起源细胞。我们假设谱系保真度的丧失是导致乳腺上皮恶性转化易感性增加的关键因素。管腔细胞中一个关键的年龄相关改变是转录因子ELF5表达的降低。ELF5对乳腺发育、维持ER−管腔上皮细胞状态至关重要，其失调在BC中被观察到。ELF5表达和启动子近端甲基化的变化可作为乳腺组织的生物学时钟。ELF5在管腔细胞中的表达随实际年龄以近似线性方式下降，这由调控结合因子和启动子近端DNA甲基化的变化所驱动。ELF5表达的年龄相关性降低，由其靶基因的改变所反映，提示ELF5的下降可能是导致谱系保真度丧失的关键事件。我们证明，ELF5时钟在平均风险女性中预测的乳腺生物学年龄与实际年龄相差在±3年以内。BRCA1、BRCA2或PALB2变异的高风险携带者相对于其实际年龄表现出10-40年的生物学年龄加速。我们假设，管腔细胞中的ELF5表达水平反映了乳腺组织对癌症的易感性，独立于导致风险增加的特定环境、表观遗传、遗传或年龄相关因素。我们提出，测量ELF5可作为BC风险的分子“矿井中的金丝雀”，或作为监测预防性干预的临床相关指标。
查看英文原文 English abstract
Aging is the most significant risk factor for breast cancer (BC). It is associated with transformative changes, notably a striking loss of lineage fidelity in luminal epithelial cells. This loss is characterized by a decline in lineage-specific gene expression and the acquisition of EMT- and myoepithelial-like features, along with increased transcriptional and methylome variability. In young women harboring pathogenic mutations in BRCA1, BRCA2, and PALB2, these aging-associated phenotypes, including loss of lineage fidelity in luminal epithelial cells, are accelerated. These changes warrant closer examination as luminal epithelial cells are the likely cells of origin for the BC subtypes most associated with aging. We hypothesize that the loss of lineage fidelity is a critical factor underlying the increased susceptibility to malignant transformation in mammary epithelia. A key age-related alteration in luminal cells is the decreased expression of the transcription factor ELF5. ELF5 is crucial for mammary gland development, maintaining the ER- luminal epithelial cell state, and its dysregulation is observed in BCs. Changes in ELF5 expression and promoter-proximal methylation serve as a biological clock for breast tissue. The expression of ELF5 decreases in luminal cells in an approximately linear fashion with chronological age, driven by changes in regulatory binding factors and promoter-proximal DNA methylation. The age-associated reduction in ELF5 expression, mirrored by alterations in its target genes, suggests that a decline in ELF5 may be a pivotal event leading to the loss of lineage fidelity. We demonstrate that the ELF5 clock predicts breast biological age within ±3 years of chronological age in women at average risk. High-risk carriers of BRCA1, BRCA2, or PALB2 variants, exhibit a biological age acceleration of 10-40 years relative to their chronological age. We hypothesize that ELF5 expression levels in luminal cells reflect the susceptibility of breast tissue to cancer, independent of specific environmental, epigenetic, genetic, or age-related factors contributing to increased risk. We propose that measuring ELF5 could serve as a molecular “canary in the coal mine” for BC risk or as a clinical correlate for monitoring preventive interventions.
利益披露 Disclosure
M. Miyano, None.