Aging leads to stochastic loss of silencing at transposons in mammary luminal epithelial cells

Luminal epithelial cells (LEps) are a key cell lineage implicated in age-related luminal breast cancers. Alterations to the epigenome are a hallmark of aging cells. However, the extent of age-associated DNA methylation alterations in LEps, and the corresponding functional consequences of these alterations, have remained unclear. We report here that aging leads to distinct methylation changes in LEps. Luminal lineage-specific genes gain promoter methylation, whereas myoepithelial-specific genes lose promoter methylation. Regulatory elements display methylation changes at lineage-specific TF binding sites consistent with the loss of lineage fidelity. CpG islands (CGIs) and transposable elements (TEs) have stochastic methylation gain and loss, respectively. PRC2 target genes that are hypermethylated in luminal breast cancer exhibit stochastic methylation increase with age. TEs with stochastic methylation loss are activated in breast cancer and potentially function as regulatory elements contributing to the loss of lineage fidelity with age. 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. SignificanceMammary luminal epithelial cells lose lineage-specific expression with age and accumulate stochastic methylation changes that lead to loss of silencing at transposable elements. These age-dependent events potentially promote breast cancer susceptibility.