STAT1 gene expression is enhanced by nuclear EGFR and HER2 via cooperation with STAT3.

Both EGFR and HER2 are important mediators of tumorigenesis and tumor progression. Despite their best-characterized roles as plasma membrane-bound receptors, both receptors undergo nuclear translocation though the impact of this process remains unclear. In this study, we provide evidence showing that EGFR upregulates expression of signal transducer and activator of transcription 1 (STAT1), a transcription factor responding to inflammatory signals and regulating genes involved in inflammatory response. EGFR regulation of STAT1 expression is primarily attributed to the nuclear activity of EGFR. The oncogenic transcription factor STAT3 binds to the STAT1 promoter and synergizes with nuclear EGFR to significantly enhance STAT1 gene expression. Structural characterization of the human STAT1 gene promoter indicates the presence of four functional STAT3-binding sites in the promoter and their importance in STAT1 co-regulation by EGFR and STAT3. The constitutively activated EGFR variant, EGFRvIII, also cooperates with STAT3 to activate the STAT1 gene promoter through the identified STAT3-binding sites within the promoter. Using human breast cancer cell lines, we further found a positive association between levels of STAT1, EGFR, and p-STAT3. Furthermore, we found that STAT1 expression is transcriptionally upregulated by HER2 and heregulin stimulation in breast cancer cells, and the level is further augmented by activated STAT3. In summary, we report in this study that STAT1 expression is upregulated by nuclear EGFR, EGFRvIII and HER2, and that STAT3 synergizes with the three receptors to further enhance STAT1 expression. These novel findings establish a novel link between the mitogenic ErbB signaling pathway and the inflammatory pathway mediated by STAT1.