The transcription factor nuclear factor-kB (NF-kB) regulates genes important for tumor invasion, metastasis and chemoresistance. Normally, NF-kB remains sequestered in an inactive state by cytoplasmic inhibitor-of-kB (IkB) proteins. NF-kB translocates to nucleus and activates gene expression upon exposure of cells to growth factors and cytokines. We and others have shown previously that NF-kB is constitutively active in a subset of breast cancers. In this study, we show that constitutive activation of NF-kB leads to overexpression of the antiapoptotic genes c-inhibitor of apoptosis 2 (c-IAP2) and manganese superoxide dismutase (Mn-SOD) in breast cancer cells. Furthermore, expression of the antiapoptotic tumor necrosis factor receptor associated factor 1 (TRAF1) and defender-against cell death (DAD-1) is regulated by NF-kB in certain breast cancer cells. We also demonstrate that NF-kB-inducible genes protect cancer cells against paclitaxel as MDA-MB-231 breast cancer cells modi®ed to overexpress IkBa required lower concentrations of paclitaxel to arrest at the G2/M phase of the cell cycle and undergo apoptosis when compared to parental cells. The eect of NF-kB on paclitaxel-sensitivity appears to be speci®c to cancer cells because normal ®broblasts derived from embryos lacking p65 subunit of NF-kB and wild type littermate embryos were insensitive to paclitaxel-induced G2/M cell cycle arrest. Parthenolide, an active ingredient of herbal remedies such as feverfew (tanacetum parthenium), mimicked the eects of IkBa by inhibiting NF-kB DNA binding activity and Mn-SOD expression, and increasing paclitaxel-induced apoptosis of breast cancer cells. These results suggest that active ingredients of herbs with anti-in¯ammatory properties may be useful in increasing the sensitivity of cancers with constitutively active NF-kB to chemotherapeutic drugs. Oncogene (2000) 19, 4159 ± 4169.