Why breast cancer becomes more deadly with age

Researchers at Georgetown’s Lombardi Comprehensive Cancer Center have identified a mechanism that may help explain a key reason why older people experience worse outcomes from breast cancer. The study implicates RAGE (Receptor for Advanced Glycation End-products), a cell surface receptor that amplifies inflammatory signaling, and which also becomes increasingly active with metastatic progression.

“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, Ph.D., 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.”

The findings appear in Communications Biology and will also be featured in the Nature portfolio special collection, Cancer and Aging.

Serendipitous opportunity to study aging

A key aspect of the study benefited from timing and chance. During COVID, because of reduced laboratory activity, some of the research team’s mouse colonies aged longer than originally planned.

This created a rare opportunity to study cancer in these older animals, which is normally a difficult and expensive endeavor. Serendipitously, the opportunity gave the scientists the ability to directly compare how tumors behave in younger versus older mice.

RAGE drives age-related metastasis

Using three different mouse models of triple-negative breast cancer, a very aggressive form of the disease, 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. This included the proteins S100 and HMGB1, found in both primary tumors and metastatic sites. These changes made it easier for cancer cells to invade and spread.

“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.

Therapeutic potential of targeting RAGE

RAGE is already being explored as a therapeutic target in several age-related diseases, highlighting its potential relevance in cancer. In prior work, the researchers had shown that the RAGE inhibitor TTP488 (azeliragon) can suppress breast cancer metastasis in preclinical models.

In the current study, they also tested the drug in the lab and found that TTP488 was able to reduce tumor cell invasiveness that was induced by blood sera from aged mice.

A clinical study is underway at Lombardi evaluating TTP488 in breast cancer patients receiving chemotherapy, with a focus on safety and cognitive outcome. The drug has demonstrated a favorable safety profile in people, making it an optimal choice for further study.

“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.”

Who’s behind this story?

Sadie Harley

BSc Life Sciences & Ecology. Microbiology lab background with pharmaceutical news experience in oil, gas, and renewable industries.

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Robert Egan

Bachelor’s in mathematical biology, Master’s in creative writing. Well-traveled with unique perspectives on science and language.

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