Aging leads to DNA methylation alterations associated with loss of lineage fidelity and breast cancer in mammary luminal epithelial cells

Abstract

AbstractAge 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.