NEW YORK – A team from the Jackson Laboratory for Genomic Medicine, UConn Health, and City of Hope has traced the gene expression and epigenetic changes that occur in individual cells during mammary gland aging in a mouse model, identifying shifts involving genes and pathways implicated in cancer development in humans.
"[W]e identified age-related signatures of mammary cells that are found in human breast tumors, suggesting that these could be linked to pre-neoplasia," co-senior and co-corresponding authors Olga Anczuków and Duygu Ucar, researchers affiliated with the Jackson Lab and UConn Health, and their colleagues wrote in Nature Aging on Monday.
For their study, the investigators turned to 10x Chromium single-cell RNA sequencing to profile gene expression and chromatin accessibility in cells from six young adult and six older mice, bringing in single-nucleus ATAC-seq profiles on samples from three mice per age group to search for cell composition, gene expression, and gene regulatory shifts related to mammary gland tissue aging.
The three-month-old mouse models correlate to a human age of around 20 to 30 years old, the team explained, while the older, 18-month-old mice were comparable to humans who are more than 55 years old.
"[W]e investigated how aging rewires transcriptomic and epigenomic programs of mouse mammary glands at single-cell resolution, yielding a comprehensive resource for aging and cancer biology," the authors explained, noting that the combined expression and chromatin accessibility profiles offered "mechanistic insights into the transcriptional programs regulating mammary aging."
In epithelial cells found in mammary gland tissue, the investigators saw shifts in the activity and regulation of genes from metabolic, pro-inflammatory, and cancer-related pathways among older mice, for example. Their results pointed to an age-related dip in fibroblast marker gene activity and an uptick in senescence markers and in the proportion of cancer-associated fibroblast cells in the stromal cell subset.
When the team considered immune cell patterns in the aging mammary gland tissue, meanwhile, it unearthed an increase in the proportion of specific T-cell subtypes and so-called M2-like macrophages in the more elderly mice, with spatial transcriptomic data pointing to an age-related co-colocalization between immune cells and epithelial cells.
Likewise, the authors explained, genes linked to senescence, inflammation, and cancer were marked by changes in both expression and chromatin accessibility in mammary gland samples from older mice.
More broadly, they also saw hints that lineage fidelity tended to decline across the epithelial, stromal, and immune cell groups in the older mice — a process that they found by following the expression of genes linked to cell identity.
"Together, these data uncover that epithelial, immune, and stromal cell shift in proportions and cell identity, potentially impacting cell plasticity, aged microenvironment, and neoplasia risk," the authors said.
Finally, by bringing in expression data on breast tumor and normal breast tissue sets from the Cancer Genome Atlas, the researchers identified hundreds of genes with upregulated or dialed-down expression in specific cell types in mammary gland tissue from the aging mouse models that overlapped with differentially expressed genes in human breast tumors, particularly tumors in the luminal A and luminal B cancer subtypes that tend to turn up in older individuals.
"Further work is needed to understand how hormonal and environmental changes impact aging of the mammary gland in model systems," the authors wrote, adding that additional research is needed to continue untangling changes and interactions in mammary gland tissue that are related to age and other biological processes such as pregnancy and menopause.