It is well known that aging brings an increased likelihood of developing cancer. What is not well understood are the cellular and molecular events that initiate the cancer. Now, researchers at the Jackson Laboratory (JAX) have created an atlas of how healthy breast tissue ages, revealing key cellular, molecular, and genetic changes that may tip the balance toward breast cancer development. The work investigates “how aging rewires transcriptomic and epigenomic programs of mouse mammary glands at single-cell resolution.” In doing so, the work establishes, for the first time, a direct link between aging-related gene expression changes and chromatin accessibility in the mammary gland. The paper also provides an open-access resource for the scientific community to explore aging and its role in increased cancer risk.

The findings are published in Nature Aging in the paper, “Comprehensive single-cell aging atlas of healthy mammary tissues reveals shared epigenomic and transcriptomic signatures of aging and cancer.”

Using single-cell and spatial transcriptomics, the researchers compared young virgin female mice to older mice and mapped how mammary gland cellular landscape changes over time. The team, led by Olga Anczukόw, PhD, an associate professor at JAX and co-program leader of the National Cancer Institute-designated JAX Cancer Center, found that epithelial, immune, and stromal cells—which are essential for maintaining healthy breast tissue—undergo shifts not just in their numbers but also in their molecular identity. Epithelial cells, which line milk ducts from which most breast cancers arise, exhibit epigenetic and transcriptional changes in genes, some of which are associated with metabolism and cancer. Stromal cells, which provide structural support to breast tissue, “downregulate fibroblast marker genes and upregulate markers of senescence and cancer-associated fibroblasts.” Immune cells infiltrate the aging tissue, but instead of protecting against cancer, these cells are prone to inflammation and exhaustion, potentially fueling tumor development.

“For the first time, we’ve linked aging-related gene expression changes in breast tissues to alterations in chromatin accessibility, the molecular ‘script’ controlling gene activity,” said Duygu Ucar, PhD, a professor at JAX. “This implies that as breast cells age, alterations in chromatin structure may play a crucial role in regulating gene activity.”

To see if these age-related molecular changes in mice reflect human breast cancer risk, Anczukόw and Ucar and their teams compared their data to genetic profiles of human breast tumors. They found that these age-related molecular signatures in mice closely mirror patterns seen in human breast cancers—suggesting that the aging breast microenvironment plays a direct role in cancer risk and can provide valuable warning signs.

“Finding these overlapping pathways was really exciting,” said Brittany Angarola, PhD, an associate research scientist at JAX. “It suggests that aging-related shifts in healthy tissue might create a more cancer-friendly environment before tumors even form.”

This open-access atlas provides a crucial resource for scientists worldwide to explore how aging influences cancer risk. The dataset allows researchers to identify potential biomarkers for early detection and develop strategies for prevention and treatment.

“This study not only advances our understanding of aging and cancer but also lays the groundwork for future research into interventions that could reduce cancer risk in aging populations,” said Anczukόw. “It provides us with a powerful tool to help cancer patients everywhere.”