Luminal epithelial cells integrate variable responses to aging into stereotypical changes that underlie breast cancer susceptibility

Effects from aging in any single cell 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. We have shown that mammary epithelia exhibit substantial stereotypical changes with age which merits attention as 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. From transcriptomic analyses of luminal and myoepithelial lineages from reduction mammoplasties, we identified two models of age-dependent changes in gene expression -- directional changes and increased variance -- that 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 frank cancers. A luminal-specific aging biomarker machine learning classifier distinguished normal tissue from breast cancers and was predictive of PAM50 breast cancer subtypes. The variability in expression of age-dependent genes across individuals may influence differential susceptibility to breast cancer initiation in a subtype-specific manner. 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. ### Competing Interest Statement The authors have declared no competing interest.