Age: More than a Demographic in Breast Cancer
Many people accept illness as an inevitable part of aging. But in breast cancer, the relationship between age and tumor biology is more complex than it may seem. Supported by one of the inaugural 2023 Victoria’s Secret Global Fund for Women’s Cancers Rising Innovator Grants, in Partnership with Pelotonia and AACR, Sandra McAllister, PhD is investigating how aging shapes breast cancer at the molecular level. Analyzing tumors from over 1,500 patients, her team, including collaborator Dr. Peter van Galen, PhD and researchers across three continents, shows that tumor biology shifts in distinct ways as patients age, and these shifts vary across major subtypes (1). In triple-negative breast cancer (TNBC), older patients’ tumors are enriched for inflammatory and stress responses and tumor cell invasive signatures, while in estrogen receptor-positive (ER+) breast cancer, tumors from older patients show decreased metabolism and immune responses.
The Victoria’s Secret Global Fund for Women’s Cancers Rising Innovator Grants, in Partnership with Pelotonia and AACR support innovative research projects in breast and gynecologic cancers and invest in promising female scientists at the associate professor level, such as Dr. McAllister. An associate professor of medicine at Harvard Medical School and associate scientist at the Brigham Women’s Hospital, Dr. McAllister hypothesizes that the changes in immune system function that occur with age have an impact on breast cancer biology. Understanding these changes can help explain why younger and older breast cancer patients have worse outcomes than middle-aged patients and aid in the design of therapeutic strategies that are more age-appropriate.
Her team first analyzed bulk gene expression in tumors from patients with stage 1-3 TNBC and ER+ breast cancer, stratified into two age groups: younger than 45 and older than 65. In TNBC patients, tumors from older patients showed increased expression of immune-and inflammation-related genes, whereas tumors from younger patients showed upregulation of genes involved in the cell cycle and cancer driving signaling pathways. On the other hand, in ER+ breast cancer, tumors from older patients had very high estrogen receptor expression but decreased expression of genes related to breast differentiation; most immune-related genes did not vary with age, except for stronger tumor necrosis factor signaling in younger patients. These patterns suggested that age-related changes in tumor biology differ across breast cancer subtypes and warranted deeper investigation.
To explore these differences at a higher resolution, the team developed ASPEN (Age Specific Program ENrichment), a pipeline designed to assess age-associated gene expression programs for every cell type present in the tumors. For this analysis, the team looked at age as a continuous variable to identify pathways that correlate with age. Using 10 TNBC and 11 ER+ samples (over 80,000 cells), they found that most age-related programs were positively associated with age in TNBC and negatively associated with age in ER+ breast cancer. The results confirmed and expanded on their bulk tumor findings.
In TNBC, the researchers found that genes associated with epithelial-mesenchymal transition (EMT), a program that promotes invasion, were enriched with increasing age in the cancer cells. Multiplex immunofluorescence on tumor tissue from independent clinical cohorts of TNBC patients confirmed this age-associated EMT signature. Also in TNBC, genes linked to immune function and inflammation were increasingly enriched with age across several cell types in the tumor microenvironment. The converse was found in ER+ breast cancer where immune responses decreased with age, mainly in the cancer cells. In ER+ breast cancers, they also found that metabolic programs inversely associated with age in many cell types, particularly the blood vessels, which they confirmed by multiplex immunofluorescence. These findings highlight how aging reshapes multiple biological pathways within the tumor microenvironment.
Taking this forward, Dr. McAllister noted that the study’s findings open new avenues for discovery and thinking about how breast cancer should be treated across the lifespan. Using an analysis program called CellChat, the team predicted ligand-receptor signaling interactions that may drive some of the age-related differences that were observed, giving them and others in the field a roadmap for further investigation. Emphasizing the broader significance of the work, she pointed out that “these findings suggest opportunities to design therapies tailored not only to tumor subtype but also to age-related factors.” Their team would also like to investigate whether processes related to accelerated biological aging may help explain early-onset breast cancer. In parallel, they are interested in integrating clinical outcome data with the ASPEN framework to better understand how the age-related molecular features relate to treatment response and patient survival. Ultimately, their goal is to translate these insights into age-informed treatments that can be tested in clinical trials.
Reflecting on her career, Dr. McAllister highlighted how AACR’s support has contributed to the evolution of her research program, beginning with the 2013 Gertrude B. Elion Cancer Research Award. She noted that early funding gave her the opportunity to develop new tools and models and to begin exploring how factors such as age influence breast cancer biology. “That early investment helped lay the foundation for the work we are now advancing through the Victoria’s Secret Rising Innovator Research Grant in Partnership with Pelotonia and AACR,” she said. “This kind of support has allowed us to pursue new ideas and build the foundations for discoveries that could ultimately improve outcomes for patients across diverse populations.” The continuity of this support is helping her team advance research that addresses the diverse needs of patients across their lifespan.
REFERENCE
- Parsons A, Sauras Colon E, Manjunath M, Zhang H, Chen J, et al. Cell populations in human breast cancers are molecularly and biologically distinct with age. Nature Aging. 2025; 5:2546-63