IRF-1 inhibits NF-B activity, suppresses TRAF2 and cIAP1 and induces breast cancer cell specific growth inhibition

Interferon Regulatory Factor (IRF)-1, originally identified as a transcription factor of the human interferon (IFN)- gene, mediates tumor suppression and may inhibit oncogenesis. We have shown that IRF-1 in human breast cancer cells results in the down-regulation of survivin, tumor cell death, and the inhibition of tumor growth in vivo in xenogeneic mouse models. In this current report, we initiate studies comparing the effect of IRF-1 in human nonmalignant breast cell and breast cancer cell lines. While IRF-1 in breast cancer cells results in growth inhibition and cell death, profound growth inhibition and cell death are not observed in nonmalignant human breast cells. We show that TNF-or IFN- induces IRF-1 in breast cancer cells and results in enhanced cell death. Abrogation of IRF-1 diminishes TNF- and IFN--induced apoptosis. We test the hypothesis that IRF-1 augments TNF--induced apoptosis in breast cancer cells. Potential signaling networks elicited by IRF-1 are investigated by evaluating the NF-B pathway. TNF-and/or IFN- results in decreased presence of NF-B p65 in the nucleus of breast cancer cells. While TNF- and/or IFN- can induce IRF-1 in nonmalignant breast cells, a marked change in NF-B p65 is not observed. Moreover, the ectopic expression of IRF-1 in breast cancer cells results in caspase-3, -7, -8 cleavage, inhibits NF-B activity, and suppresses the expression of molecules involved in the NF-B pathway. These data show that IRF-1 in human breast cancer cells elicits multiple signaling networks including intrinsic and extrinsic cell death and down-regulates molecules involved in the NF-B pathway.