Aging promotes a RAGE-dependent increase in breast cancer metastasis.

Breast cancer incidence and mortality increase with age, but the mechanisms linking aging to metastasis remain unclear. Most preclinical studies use young animal models, limiting insight into how the aged microenvironment influences cancer. Here, we show that aging markedly increases breast cancer metastasis in multiple mouse models, and this effect is dependent on host expression of the Receptor for Advanced Glycation End-products (RAGE). Aging increased tumor RAGE ligand levels, including S100A8/9 and AGEs, and induced RAGE-dependent changes in inflammatory, EMT, angiogenic, and extracellular matrix gene programs in tumors. Circulating cytokines and S100A8/9 from aged hosts promoted tumor cell invasion, which was suppressed by RAGE or S100A8/9 inhibition. In human breast cancers, elevated AGER expression and enrichment of aging- and RAGE-associated transcriptional signatures correlated with poorer survival, especially in older patients. These findings identify RAGE as a mechanistic link between aging and metastasis and a potential therapeutic target in older patients.