AbstractRecently, we reported that epidermal growth factor receptor (EGFR) induce expression of a module of genes known to be inducible by interferons and particularly interferon‐γ. Here we show that the module is tightly regulated by EGFR in the 2 human cancer cell lines that overexpress EGFR, A431 and HN5. The module of genes included the tumor suppressor IRF‐1, which was used as a prototypical member to further investigate the regulation and function of the module. Ligand‐activated EGFR induce expression of IRF‐1 via phosphorylation of STAT1 and STAT3. In contrast, cells expressing the constitutively active cancer specific receptor EGFRvIII are unable to mediate phosphorylation of these STATs and thereby incapable of inducing IRF‐1. We also demonstrate that IRF‐1 is expressed in an EGF dose‐dependent manner, which correlates with inhibition of cell proliferation, and that the regulation of IRF‐1 is partially dependent on intracellular Src family kinase activity. Treatment with the dual specific Abl/c‐Src kinase inhibitor AZD0530 significantly reduces the growth inhibitory effect of high EGF concentrations, signifying that EGFR induced IRF‐1 is responsible for the observed growth inhibition. In addition, we show that media from these EGF treated cancer cells upregulate the activation marker CD69 on both B‐cells and T‐cells in peripheral blood. Taken together, these results suggest that cells acquiring sustained high activity of oncogenes such as EGFR are able to activate genes, whose products mediate growth arrest and activate immune effector cells, and which potentially could be involved in alerting the immune system in vivo leading to elimination of the transformed cells. © 2007 Wiley‐Liss, Inc.