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.

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Several angiogenic factors and extracellular matrix-degrading enzymes that promote invasion and metastasis of cancer are produced by stromal fibroblasts that surround cancer cells. The expression of genes that code for some of these proteins is regulated by the transcription factor NF-B. In this report, we demonstrate that conditioned medium (

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In this series patients who underwent early radical surgery because of poor prognostic features found at LE had good overall and cancer-specific long-term survival. Even after neoadjuvant therapy, more than a third of patients had residual disease at the time of radical surgery. We therefore recommend radical surgery with neoadjuvant therapy when poor prognostic features are found at LE.