Scientists have uncovered a biological mechanism that may help explain why breast cancer becomes more dangerous with age.
In older mice, breast cancer was far more likely to spread to the lungs, even when the original tumors grew at roughly the same rate as those in younger animals. Researchers at Georgetown’s Lombardi Comprehensive Cancer Center have identified an inflammation-related receptor that appears to play a central role in this age-related increase in metastasis.
The researchers found that genetically removing the receptor, known as RAGE, almost completely eliminated the increased spread of cancer in older mice. Published May 15, 2026, in Communications Biology, the findings suggest that changes occurring throughout the body during aging can influence how aggressively cancer behaves.
How Aging Creates Conditions That Help Cancer Spread
The study focused on RAGE (Receptor for Advanced Glycation End-products), a receptor on the surface of cells that amplifies inflammatory signals. Aging increased levels of molecules that activate RAGE, including the proteins S100 and HMGB1. These molecules were found in both primary tumors and metastatic sites, where the resulting inflammatory activity helped cancer cells invade surrounding tissues and spread.
“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,” says Barry Hudson, PhD, associate professor of oncology at Georgetown Lombardi and corresponding author for this article. “Most laboratory studies rely on young mice, which has limited our understanding of how aging itself alters the host environment, including immune function and chronic inflammatory states that, in turn, influence cancer behavior.”
“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.”
An Unexpected Opportunity to Study Cancer in Older Animals
The research benefited from an unusual circumstance during the COVID-19 pandemic. Reduced laboratory activity meant some mouse colonies were allowed to age longer than originally planned. Because maintaining older laboratory mice is expensive and time-consuming, the situation gave researchers a rare opportunity to examine how aging affects cancer progression. They compared younger and older animals across three mouse models of triple-negative breast cancer, an aggressive form of the disease.
The team also investigated whether the findings had parallels in humans. An analysis of breast cancer data from more than 1,000 patients showed that higher expression of AGER (the gene encoding RAGE), along with elevated activity in related inflammatory genes, was associated with poorer outcomes. Although these associations do not establish that RAGE causes metastasis in patients, they support the potential clinical relevance of the animal experiments.
A Potential Treatment Target Already Under Investigation
RAGE is being studied as a therapeutic target in several diseases associated with aging. Earlier research from the Georgetown team showed that the RAGE inhibitor TTP488 (azeliragon) could suppress breast cancer metastasis in preclinical models. In the latest experiments, the drug also reduced the invasiveness of cancer cells exposed to blood serum from aged mice, which otherwise promoted more invasive behavior.
A clinical study at Georgetown Lombardi is now evaluating TTP488 in breast cancer patients undergoing chemotherapy, with particular attention to safety and cognitive outcomes. The drug has previously demonstrated a favorable safety profile in humans, although its ability to prevent breast cancer metastasis in patients remains unproven.
“This study highlights the importance of the host environment in cancer. 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,” says Hudson. “Most deaths due to cancer occur because tumors spread to other organs, so understanding these influences may help identify new strategies to limit metastasis.”
Reference: “Aging promotes a RAGE-dependent increase in breast cancer metastasis” by Philip Miller, Sunita Chopra, Melinda Magna, Jiaxiang Tao, Carlos Benitez, Thomas Heist, Nanette H. Bishopric, Jeanne S. Mandelblatt, Julia Panov, Joyce M. Slingerland and Barry I. Hudson, 15 May 2026, Communications Biology.
DOI: 10.1038/s42003-026-10022-4
Never miss a breakthrough: Join the SciTechDaily newsletter.
Follow us on Google and Google News.