Age Amplifies Breast Cancer Metastasis Through Inflammatory Pathways

In 2019, oncology researcher Barry Hudson moved his laboratory from the University of Miami to Georgetown University, just before the COVID‑19 pandemic curtailed many research activities. When the lab resumed work, most of the mice had reached more than one year of age, providing an unexpected opportunity to study cancer in older animals—relevant because older adults often experience poorer outcomes in breast cancer.

Traditionally, breast cancer studies use two- to three‑month‑old mice, equivalent to 15–20‑year‑old humans. Hudson noted that the biology of cancers in older mice remains poorly understood.

Using aged mice, Hudson’s team found that aging markedly increases breast cancer metastasis via the receptor for advanced glycation end‑products (RAGE), a pro‑inflammatory molecule that contributes to tumor progression. Their study, published in Communications Biology, demonstrates how a changing host environment with age can accelerate cancer aggression and identifies potential therapeutic targets for older patients.

Frances Turrell, a cancer biologist at Manchester Cancer Research Centre, emphasized that this work underscores the need to study breast cancer metastasis in aged settings to fully capture age‑related mechanisms.

For the experiment, Hudson’s group implanted various breast cancer cell types into young (three‑month‑old) and aged (21‑month‑old) mice. Aged mice exhibited significantly higher lung metastasis, even when primary tumor growth was comparable to that of younger animals. Hudson described the findings as both expected and striking.

The team focused on RAGE, known to enhance tumor cell survival and invasion. When they introduced tumors into aged mice lacking the RAGE gene, metastasis was markedly reduced compared to wild‑type controls. They also observed elevated levels of RAGE ligands in tumors and metastatic tissue of older mice, localized mainly with myeloid immune cells – indicating that host cells, rather than tumor cells, produce these ligands in aging.

Fluorescence microscopy revealed increased secretion of pro‑inflammatory and tumor‑promoting cytokines in aged wild‑type mice, a response absent in RAGE‑knockout animals. These results confirm a critical role for host RAGE in establishing a pro‑metastatic tumor microenvironment in aged hosts.

To assess clinical relevance, Hudson and colleagues analyzed data from over 1,000 breast cancer patients, finding that higher RAGE expression correlated with poorer outcomes, especially in women over 55. This suggests that targeting RAGE could provide benefits specifically for older patients, whose immune environments differ from those modeled in young mice.

Turrell acknowledged that while the study focused on lung metastasis, breast cancer commonly spreads to bone, liver, and brain, and future work should explore these sites. She also noted that whole‑body RAGE knockout models complicate pinpointing the exact cellular contributors, a limitation the researchers plan to address in subsequent studies.

Hudson proposes further investigation of drugs targeting RAGE and deeper mechanistic studies to understand age‑associated metastasis fully. He emphasizes that although age itself cannot be altered, targeting age‑related molecular pathways may improve therapeutic responses in older cancer patients.

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