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Overexpression of IRF9 Confers Resistance to Antimicrotubule Agents in Breast Cancer Cells¹

Departments of Radiology [K. E. L., C. M. P., D. P-W.], Molecular Biology and Pharmacology [K. E. L., C. M. P., D. P-W.], and Pathology and Immunology [R. D. S.], Washington University Medical School, St. Louis, Missouri 63110

IRF9/p48/ISGF3 (IRF9) is an IFN regulatory factor that mediates signalingby type I IFNs (IFN and IFNß). After single-step selection of breastadenocarcinoma cells in paclitaxel, differential display and single gene analysis demonstrated that transcriptional activation of IRF9 and other 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 IFN-responsive genes. However, drug resistance was not induced by overexpression of Stat1 or Stat2, or treatment with IFN per se. Using a donor-matched array of cDNA prepared from human tumor and normal tissue from a variety of organs, we observed overexpression of IRF9 in approximately one-half of breast and uterine 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 cells and may link downstream mediators of IFN signaling to drug resistance in human cancers.

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