Overexpression of IRF9 confers resistance to antimicrotubule agents in breast cancer cells

yIRF9/p48/ISGF3 gamma (IRF9) is an IFN regulatory factor that mediates sign aling by type I IFNs (IFN alpha and IFN beta). After single-step selection of breast adenocarcinoma cells in paclitaxel, differential display and sing le gene analysis demonstrated that transcriptional activation of IRF9 and o ther IFN-responsive genes, independent of IFN, corresponded with resistance to antimicrotubule agents. Transient overexpression of IRF9 reproduced the drug-resistance phenotype and induced expression of ITN-responsive genes. However, drug resistance was not induced by overexpression of Stat1 or Stat 2, or treatment with IFN alpha per se. Using a donor-matched array of cDNA prepared from human tumor and normal tissue from a variety of organs, we ob served overexpression of IRF9 in approximately one-half of breast and uteri ne tumors, which indicated that IRF9 may be important in signaling in these tumor types. These data identify a novel IFN-independent role for IRF9 in the development of resistance to antimicrotubule agents in breast tumor cel ls and may link downstream mediators of IFN signaling to drug resistance in human cancers.