Fig. 1

Downstream IFNα signaling in IBC. a Canonical IFNα signaling begins with IFNα binding to IFNAR1/IFNAR2 receptor. After it binds to the receptor, JAK1 and TYK2 cross-phosphorylate each other and phosphorylate the intracellular domains of the receptors to allow for STAT1 and STAT2 binding through their SH2 domain for subsequent phosphorylation. Once STAT dimers form, they translocate into the nucleus and bind to their respective DNA binding elements. IRF9 and STAT1 are the only two proteins that directly interact with the DNA whereas STAT2 is necessary for stabilizing the ISGF3 complex and further recruitment of co-activators. b During chronic IFNα signaling, STAT proteins are no longer robustly phosphorylated however the interferon signature may remain upregulated due to the similarity between ISGF3 and U-ISGF3. In the absence of IFNα, there will either be no signal or, depending on STAT2 and IRF9 levels, the interferon response may stay elevated due to the continued formation of STAT2 and IRF9. TN-IBC cells have robust levels of IRF9 and IRF9 increases in tumor clusters. Therefore, IRF9 could be the key driver of this response. Adapted from [19]