RAGE Implicated in Worsening Breast Cancer Mortality with Age

Researchers at Georgetown’s Lombardi Comprehensive Cancer Center have identified a mechanism that may help to explain why older people experience worse outcomes from breast cancer. The study in different mouse breast cancer models and in human breast cancers 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. The study findings in addition suggested that inhibiting RAGE may offer a well-tolerated adjunctive breast cancer therapy in older patients.

“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,” said Barry Hudson, PhD, associate professor of oncology at Georgetown Lombardi. “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.” Hudson is corresponding author of the researchers’ Communications Biology published paper titled “Aging promotes a RAGE-dependent increase in breast cancer metastasis.” In their paper the authors concluded that their findings “… identify RAGE as a mechanistic link between aging and metastasis and a potential therapeutic target in older patients.” They say the findings will also be featured in the Nature portfolio special collection, Cancer and Aging.

Age is the primary risk factor for the development of adult cancers, including breast cancer, with almost half of new breast cancer diagnoses and more than half of breast cancer-specific deaths occurring in women aged 65 years and older, the authors wrote. And while advances in screening and therapy have improved survival, older women continue to have higher breast cancer-specific mortality. “Despite accumulating evidence that metastasis in murine breast cancer models increases with advancing host age, the mechanisms underlying this have not been elucidated, highlighting the need for further mechanistic studies,” the team continued.

And while breast cancer is more prevalent in older women, most cancer research in mouse models has used young, 2–3-month-old adult mice, which are about equivalent in age to 15–20-year-old humans. Timing and chance presented Hudson and colleagues with opportunities to carry out their newly reported study. During COVID, when there was reduced laboratory activity, some of the research team’s mouse colonies aged longer than originally planned. This created a rare opening to study cancer in these older animals—normally a difficult and expensive endeavor—giving the scientists the ability to directly compare how tumors behave in younger versus older mice.

RAGE is a proinflammatory molecule that is being considered as a therapeutic target in multiple aging-related diseases, including various cancers, cardiovascular and neurodegenerative diseases.

Using three different mouse models of triple-negative breast cancer (TNBC), the researchers discovered that aged mice developed substantially more lung metastases than younger mice, despite similar primary tumor growth. The team then showed that genetic deletion of RAGE in mice almost completely eliminated this age-related surge in metastasis.

Through their studies, the team demonstrated that aging increased levels of inflammatory molecules that activate RAGE. These included the proteins S100 and HMGB1, found in both primary tumors and at 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,” said Hudson. “RAGE appears to be a key mediator of these harmful age-related pathways.” In their paper the authors stated that their data “… suggest that aging promotes multiple prometastatic processes within the tumor and its microenvironment, and that RAGE is required for the induction of these inflammatory and tumor-promoting pathways in aged hosts.“

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 their findings. They noted, “… in human breast cancers, high AGER expression, as well as enrichment for mouse tumor-derived aging- and RAGE-associated gene signatures, predicted poorer outcomes, particularly in older women …Together, these data indicate that in older individuals with breast cancer, intratumor RAGE overexpression amplifies aging-associated transcriptional programs, linking age-dependent inflammation to promote metastatic progression.”

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.” Pharmacologic inhibition of RAGE by TTP488 (PF-04494700 or azeliragon) suppressed migration and invasion towards aged serum, further supporting the requirement of RAGE signaling for age-dependent metastasis,” the team noted.

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. “TTP488 has demonstrated an excellent safety profile in Phase I/II clinical studies in older adults with Alzheimer’s disease, supporting its potential for repurposing,” the authors wrote. “Therapeutic RAGE inhibition may provide a well-tolerated means to counteract inflammaging and improve cancer outcomes in the elderly, who often face limited treatment options due to toxicity,” the investigators wrote.

“This study highlights the importance of the host environment in cancer,” Hudson added. “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,” said 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.”

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