Effects from aging in single cells are unpredictable, whereas aging phenotypes at the organ- and tissue-levels tend to appear as stereotypical changes. The mammary epithelium is a bilayer of two major phenotypically and functionally distinct cell lineages, the luminal epithelial and myoepithelial cells. Mammary epithelia exhibit substantial stereotypical changes with age that merits attention because they are putative breast cancer-cells-of-origin. We hypothesize that effects from aging that impinge upon maintenance of lineage fidelity increases susceptibility to cancer initiation. We identified two models of age-dependent changes in gene expression, directional changes and increased variance, which contributed to genome-wide loss of lineage fidelity. Age-dependent variant responses were common to both lineages, whereas directional changes were almost exclusively detected in luminal epithelia and implicated downregulation of chromatin and genome organizers such as SATB1. Epithelial expression of gap junction protein GJB6 increased with age, and modulation of GJB6 expression in heterochronous co-cultures revealed that it provided a communication conduit from myoepithelial cells that drove directional change in luminal cells. Age-dependent luminal transcriptomes comprised a prominent signal detectable in bulk tissue during aging and transition into cancers. A machine learning classifier based on luminal-specific aging distinguished normal from cancer tissue and was predictive of breast cancer subtype. We speculate that luminal epithelia are the ultimate site of integration of the variant responses to aging in their surrounding tissue and that their emergent aging phenotype both endows cells with the ability to become cancer-cells-of-origin and embodies a biosensor that presages cancer susceptibility.

中文翻译：

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管腔上皮细胞将对衰老的可变反应整合到构成乳腺癌易感性的刻板印象变化中

单细胞衰老的影响是不可预测的，而器官和组织水平的衰老表型往往表现为刻板的变化。乳腺上皮细胞是由两种主要的表型和功能不同的细胞谱系、管腔上皮细胞和肌上皮细胞组成的双层。乳腺上皮细胞随着年龄的增长表现出明显的刻板印象变化，这值得关注，因为它们是假定的乳腺癌细胞来源。我们假设影响谱系保真度维持的衰老影响增加了对癌症发生的易感性。我们确定了基因表达的年龄依赖性变化、方向变化和方差增加的两种模型，这导致了全基因组谱系保真度的丧失。年龄依赖性变异反应对两个谱系都很常见，而定向变化几乎只在管腔上皮细胞中检测到，并且与染色质和基因组组织者（如 SATB1）的下调有关。间隙连接蛋白 GJB6 的上皮表达随着年龄的增长而增加，并且异时共培养物中 GJB6 表达的调节表明它提供了来自肌上皮细胞的通讯管道，从而驱动管腔细胞的方向变化。年龄依赖性管腔转录组包含在衰老和转变为癌症期间在大块组织中可检测到的显着信号。基于管腔特异性老化的机器学习分类器可区分正常组织和癌组织，并可预测乳腺癌亚型。