Interferon regulatory factor-8 (IRF8), originally identified as a leukemic
tumor suppressor, can also exert anti-neoplastic activities in solid
tumors. We previously showed that IRF8-loss enhanced
tumor growth, which was accompanied by reduced
tumor-cell susceptibility to apoptosis. However, the impact of IRF8 expression on
tumor growth could not be explained solely by its effects on regulating apoptotic response. Exploratory gene expression profiling further revealed an inverse relationship between IRF8 and MMP3 expression, implying additional intrinsic mechanisms by which IRF8 modulated neoplastic behavior. Although MMP3 expression was originally linked to
tumor initiation, the role of MMP3 beyond this stage has remained unclear. Therefore, we hypothesized that MMP3 governed later stages of disease, including progression to
metastasis, and did so through a novel IRF8-MMP3 axis. Altogether, we showed an inverse mechanistic relationship between IRF8 and MMP3 expression in
tumor progression. Importantly, the growth advantage due to IRF8-loss was significantly compromised after silencing MMP3 expression. Moreover, MMP3-loss reduced spontaneous lung
metastasis in an orthotopic mouse model of mammary
carcinoma. MMP3 acted, in part, in a cell-intrinsic manner and served as a direct transcriptional target of IRF8. Thus, we identified a novel role of an IRF8-MMP3 axis in
tumor progression, which unveils new therapeutic opportunities.