Abstract
To determine whether innate immune-sensing activity is associated with epithelial–mesenchymal transition (EMT) and related tumor-aggressiveness programs in human breast cancer. We analyzed RNA sequencing and clinical data from The Cancer Genome Atlas breast cancer cohort (
n
= 1087). Gene expression-based signatures were constructed for innate immune sensing, interferon signaling, CD8 T cells, macrophages, EMT, invasion, and metastasis. Associations were evaluated using Pearson correlation, Cox proportional hazards models, and multivariable linear regression, including adjustment for PAM50 molecular subtype and immune cell signatures. Innate immune-sensing signatures were strongly correlated with interferon signaling (
r
= 0.73) and macrophage-associated signatures (
r
= 0.77), indicating a coordinated inflammatory program. Innate immune sensing was moderately associated with EMT (
r
= 0.48), invasion (
r
= 0.45), and metastasis-related transcriptional programs (
r
= 0.48). In multivariable models, innate immune sensing remained associated with EMT after adjustment for molecular subtype and immune cell signatures (
β
= 0.17,
P
β
= 0.51,
P
−16
) and CD8 signatures were inversely associated (
β
= −0.14,
P
< 0.001). No association with overall survival was observed. Innate immune-sensing signatures are associated with macrophage-driven EMT programs in breast cancer, consistent with activation of inflammatory pathways within the tumor microenvironment.