Researchers at Georgetown’s Lombardi Comprehensive Cancer Centre 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 signalling, and which also becomes increasingly active with metastatic progression.

“Our study addresses a major gap by showing that ageing 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 ageing itself alters the host environment, including immune function and chronic inflammatory states that, in turn, influence cancer behaviour.”

The finding appeared, in the Nature journal Communications Biology and will also be featured in the Nature portfolio special collection, Cancer and Ageing.

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 endeavour.

Serendipitously, the opportunity gave the scientists the ability to directly compare how tumours behave in younger versus older mice.

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 tumour growth.

Genetic deletion of RAGE in mice almost completely eliminated this age-related surge in metastasis. In their studies, ageing increased levels of inflammatory molecules that activate RAGE.

This included the proteins S100 and HMGB1, found in both primary tumours and metastatic sites. These changes made it easier for cancer cells to invade and spread.

“These findings show that ageing doesn’t just increase cancer risk — it actively changes the body in ways that help tumours spread,” says Hudson. “RAGE appears to be a key mediator of these harmful age-related pathways.”

The team also analysed 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, 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 tumour 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 favourable 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 tumour cells, systemic factors such as ageing and inflammation play a critical role in shaping how cancers behave,” says Hudson.

“Most deaths due to cancer occur because tumours spread to other organs, so understanding these influences may help identify new strategies to limit metastasis.”

Article: Aging promotes a RAGE-dependent increase in breast cancer metastasis

Source: Georgetown University Medical Center