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• W4237347847 abstract "Late grade/stage tumors are generally more resistant to apoptosis, less restricted in cell cycle checkpoint controls, and better adapted to hypoxia. A key factor that provides resistance to apoptosis is transcription factor NF-kB, which is strongly elevated in breast cancers (and others) with advancing tumor progression. Elevated levels of NF-kB, as found in many advanced tumors, can prevent apoptosis by TNF, chemotherapy and irradiation. Studies were conducted to determine whether the activity of NF-kB is elevated with increasing tumor stage/grade in intraductal breast cancer (IDC) cell lines derived from primary tumors, whether inflammatory cytokines can select for cells unregulated in NF-kB and whether inhibition of NF-kB preferentially sensitizes these cells to killing by pro-apoptotic modalities. Studies were carried out using IDC cell lines derived from tumors of stages I to IV, obtained from the ATCC. The effect of NF-kB inhibition on sensitization to cell killing was determined by treatment of cells with the cyclopentanone prostaglandin PGA1, which inhibits NF-kB activating kinases IKKa/b, or by transfection with the super-repressor inhibitor of NF-kB, IkB-SR. Cells were then treated with increasing levels of TNF up to 100 ng/ml, mock irradiated (0 Gy) or irradiated at 2, 4, 6 or 8 Gy, and cell viability was measured by clonogenic and MTT assays. Selection of TNF resistance in stage II derived cell lines was carried out by cultivation for 1 month in 50 ng/ml TNF. The small number of resistant cells were pooled and expanded, passaged for 10 generations in the absence of TNF then tested for NF-kB activity and resistance to killing by hypoxia, high levels of TNF or irradiation using mock irradiated (0 Gy) or irradiated at 2, 4, 6 or 8 Gy. IL-1 inducible NF-kB activity was minimally evident in stage I and II IDC cells, but was increased 10–20 fold in stage III and IV derived IDC cell lines. Low stage (I, II) IDC cell lines were acutely sensitive to killing by hypoxia (0.5% oxygen), by as little as 2 Gy irradiation, or by low levels (10–50 ng/ml) of TNF, whereas high stage III and IV cell lines were largely unaffected under these conditions (p < 0.001). Inhibition of NF-kB had little effect on early stage cell viability, but sensitized late stage IDC cells to killing by TNF and irradiation, to a similar extent previously observed in early stage derived cells. NF-kB ablation did not significantly increase sensitivity to hypoxia mediated cell killing in any of the stage-derived cell lines, but did decrease cellular proliferation rates as shown by a reduction from approximately 26% to 16% in the proportion of stage III and IV derived cell lines in S-phase (p < 0.05). TNF-selected cells displayed stable acquisition of elevated inducible NF-kB activity (5–10 fold), and now resembled stage III derived cells with respect to resistance to killing by irradiation or TNF and cellular proliferation rates (p < 0.01). Importantly the acquired resistance of cell lines could be reversed by inhibition of NF-kB through overexpression of the IkB-SR inhibitor, demonstrating that cell lines acquired resistance to irradiation by upregulation of NF-kB through TNF selection. TNF-selected cells displayed an increase in transformation potential as measured by anchorage independent growth in soft agar, and a 10% increase in the S-phase population of cells. These results suggest that tumor infiltrating macrophages, a major source of TNF in the tumor-stroma matrix of breast cancers, and a poor prognostic indicator, may actually select for cancer cells that overexpress NF-kB, leading to greater cancer cell survival which enables acquisition of increasingly malignant genetic alterations, as well as resistance to irradiation and chemotherapy" @default.
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• W4237347847 date "2004-09-01" @default.
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• W4237347847 title "Tnf can select for upregulated NF-kB in breast cancer progression, providing resistance to apoptosis and radiation" @default.
• W4237347847 doi "https://doi.org/10.1016/s0360-3016(04)01447-6" @default.
• W4237347847 hasPublicationYear "2004" @default.
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