Researchers at Georgetown's Lombardi Comprehensive Cancer Center have identified a mechanism that may help explain why older people experience worse outcomes from breast cancer. Their study, published in Communications Biology and featured in Nature's special collection on Cancer and Aging, reveals that aging dramatically increases breast cancer metastasis and this effect depends on the receptor RAGE (Receptor for Advanced Glycation End-products). According to associate professor Barry Hudson, Ph.D., "Our study addresses a major gap by showing that aging dramatically increases breast cancer metastasis and that this effect depends on RAGE, a receptor on the surface of cells that fuels inflammation."

The key aspect of the study benefited from timing and chance. During the COVID-19 pandemic, laboratory activity was reduced, which allowed some of the research team's mouse colonies to age longer than originally planned. This created an opportunity to directly compare how tumors behave in younger versus older mice using three different mouse models of triple-negative breast cancer.

The researchers found that aged mice developed substantially more lung metastases than younger mice, despite similar primary tumor growth. Genetic deletion of RAGE in mice almost completely eliminated this age-related surge in metastasis. In their studies, aging increased levels of inflammatory molecules that activate RAGE, including the proteins S100 and HMGB1, found in both primary tumors and metastatic sites.

"These findings show that aging doesn't just increase cancer risk - it actively changes the body in ways that help tumors spread," says Hudson. "RAGE appears to be a key mediator of these harmful age-related pathways."

The team also analyzed breast cancer data from more than 1,000 patients and found that higher expression of AGER (the gene encoding RAGE) and related inflammatory gene signatures were associated with worse outcomes in patients, supporting the clinical relevance of these findings.

RAGE is already being explored as a therapeutic target in several age-related diseases. In prior work, Hudson's team had shown that the RAGE inhibitor TTP488 can suppress breast cancer metastasis in preclinical models. The drug has demonstrated a favorable safety profile in people and is currently under evaluation at Lombardi for its effects on breast cancer patients receiving chemotherapy.

"This study highlights the importance of the host environment in cancer," says Hudson. "While cancer is often viewed as driven primarily by mutations intrinsic to tumor cells, systemic factors such as aging and inflammation play a critical role in shaping how cancers behave."

The findings suggest that targeting RAGE could be a promising therapeutic approach for breast cancer patients, particularly those with aggressive forms of the disease.

Publication details: Aging promotes a RAGE-dependent increase in breast cancer metastasis Communications Biology (2026)

DOI: 10.1038/s42003-026-10022-4

Journal information: Communications Biology, Nature

Key medical concepts: Rage, Triple-Negative Breast Carcinoma, Inflammation, HMGB1 Protein

Clinical categories: Oncology, Women's health, Healthy aging