Researchers at Georgetown’s Lombardi Comprehensive Cancer Center have identified a mechanism that may help explain a key reason why older adults experience worse outcomes from breast cancer.
This study implicates RAGE (receptor for advanced glycation end products), a cell surface receptor that amplifies inflammatory signaling, and this receptor becomes further activated as metastasis progresses.
Our study addresses a major gap by showing that breast cancer metastasis increases dramatically with age and that this effect is dependent on RAGE, a cell surface receptor that promotes inflammation. Because most laboratory studies rely on young mice, there is limited understanding of how aging itself changes the host environment, such as immune function and chronic inflammatory conditions, which in turn influences cancer behavior. ”
Dr. Barry Hudson, Lead Study Author, Associate Professor of Oncology, Georgetown University
The findings were published in the journal Nature on May 15, 2026. communication biology It will also be featured in the Nature Portfolio Special Collection. cancer and aging.
Important aspects of the study benefited from timing and chance. Due to reduced laboratory activity during the coronavirus outbreak, some of the research team’s mouse colonies ended up aging longer than originally planned. This has created a unique opportunity to study cancer in these older animals, which is usually a difficult and expensive study. Coincidentally, this opportunity allowed scientists to directly compare how tumors behave in young and old mice.
Using three different mouse models of triple-negative breast cancer, a highly aggressive disease, researchers found that older mice had significantly more lung metastases than younger mice, despite similar growth of the primary tumor. Genetic deletion of RAGE in mice almost completely eliminated this age-related proliferation of metastases.
In their study, aging increased levels of inflammatory molecules that activate RAGE. This included proteins S100 and HMGB1, which are 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 not only increases cancer risk, but also actively changes the body in ways that help tumors spread,” Hudson said. “RAGE appears to be an important mediator of these deleterious age-related pathways.”
The team also analyzed breast cancer data from more than 1,000 patients and found that increased expression of AGER (the gene encoding RAGE) and a related inflammatory gene signature were associated with worse patient outcomes, supporting the clinical relevance of these findings.
RAGE has already been investigated as a therapeutic target for several age-related diseases, highlighting its potential association with cancer. Researchers had previously shown in a previous study that the RAGE inhibitor TTP488 (azeriragon) could suppress breast cancer metastasis in preclinical models. The current study also tested the drug in the laboratory and found that TTP488 could reduce tumor cell invasion induced by serum in older mice.
Lombardi has ongoing clinical studies evaluating TTP488 in breast cancer patients receiving chemotherapy, with a focus on safety and cognitive outcomes. The drug has shown a good safety profile in humans, making it an excellent choice for further studies.
“This study highlights the importance of the host environment in cancer. Although cancer is often seen to be primarily driven by mutations inherent in tumor cells, systemic factors such as aging and inflammation play an important role in shaping cancer behavior,” Professor Hudson says. “Most cancer deaths occur because tumors spread to other organs, so understanding these effects could help identify new strategies to limit metastasis.”
