Loss of IRF5 increases ribosome biogenesis leading to alterations in mammary gland architecture and metastasis.

Despite the progress made in identifying cellular factors and mechanisms that predict progression and metastasis, breast cancer remains the second leading cause of death for women in the US. Using The Cancer Genome Atlas and mouse models of spontaneous and invasive mammary tumorigenesis, we identified that loss of function of interferon regulatory factor 5 (IRF5) is a predictor of metastasis and survival. Histologic analysis of Irf5 -/- mammary glands revealed expansion of luminal and myoepithelial cells, loss of organized glandular structure, and altered terminal end budding and migration. RNA-seq and ChIP-seq analyses of primary mammary epithelial cells from Irf5 +/+ and Irf5 -/- littermate mice revealed IRF5-mediated transcriptional regulation of proteins involved in ribosomal biogenesis. Using an invasive model of breast cancer lacking Irf5 , we demonstrate that IRF5 re-expression inhibits tumor growth and metastasis via increased trafficking of tumor infiltrating lymphocytes and altered tumor cell protein synthesis. These findings uncover a new function for IRF5 in the regulation of mammary tumorigenesis and metastasis. Highlights: Loss of IRF5 is a predictor of metastasis and survival in breast cancer.IRF5 contributes to the regulation of ribosome biogenesis in mammary epithelial cells.Loss of IRF5 function in mammary epithelial cells leads to increased protein translation.