Aging promotes a RAGE-dependent increase in breast cancer metastasis

Age is a major risk factor for the development and progression of breast cancer, yet older individuals (>65 years) are frequently excluded from clinical trials, leading to a gap in knowledge and treatment strategies. Preclinical studies rarely use aged animal models, overlooking the crucial role of aging mechanisms such as reduced immune function. Aging induced immune dysfunction is caused by an increase in myeloid and immunosuppressive cells, leading to a chronic inflammatory state known as inflammaging, leading to increased tumor progression and metastasis. The Receptor for Advanced Glycation End-products (RAGE), a proinflammatory molecule, is implicated in aging-related diseases including cancer. Using syngeneic breast cancer mouse models, we observed that tumors metastasized more extensively in aged wild-type mice compared to young mice. RAGE knockout in aged mice reduced tumor progression and metastasis, and showed reduced levels of RAGE ligands S100A8 and S1000A9 and AGEs. Transcriptomic and proteomic analyses revealed that aging promotes a proinflammatory and prometastatic tumor environment through RAGE-dependent mechanisms, highlighting RAGE as a potential therapeutic target for older breast cancer patients. These findings suggest that targeting RAGE may offer a safer therapeutic approach for mitigating metastasis in older breast cancer patients, addressing a critical need for effective treatments in this underrepresented age group.