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DNA Damage and Cellular Stress Responses

Acquisition of Stable Inducible Up-Regulation of Nuclear Factor-B by Tumor Necrosis Factor Exposure Confers Increased Radiation Resistance without Increased Transformation in Breast Cancer Cells

Departments of ¹ Microbiology and ² Radiation Oncology, New York University School of Medicine, New York, New York

Requests for reprints: Robert J. Schneider, New York University School of Medicine, 550 First Avenue, New York, NY 10016. Phone: 212-263-6006; Fax: 212-263-8276; E-mail: schner01{at}med.nyu.edu.

High-grade breast cancers are better adapted to hypoxia and more resistant to chemotherapy and radiotherapy. Constitutive activation of the transcription factor nuclear factor-B (NF-B) increases in breast tumors and in breast cancer cell lines, where it promotes chemoradiation resistance, in part by activation of antiapoptotic genes. The role for up-regulation of NF-B in breast cancer progression is less clear. Here, we first show that whereas the constitutive activity of NF-B is incrementally elevated from immortalized breast epithelial to frank transformed invasive ductal breast cancer cell lines (3-fold, ±0.1-fold, P < 0.05), inflammatory cytokine-inducible activity is further increased (up to 9-fold, ±0.9-fold, P < 0.05). We then show that inhibition of NF-B activity selectively sensitizes transformed but not immortalized cells to killing by ionizing radiation or low levels of tumor necrosis factor (TNF) by up to 10-fold (±1-fold, P < 0.05) but has little effect on hypoxia-mediated cell death. Prolonged cultivation of immortalized and partially transformed cells in TNF selected for cells displaying stable constitutive and strongly inducible overexpression of NF-B even in the absence of TNF. Stable acquisition of increased NF-B activity conferred resistance to ionizing radiation or inflammatory cytokines, which was dependent on elevated NF-B activity, but had no effect on transformation potential measured by in vitro and in vivo parameters. Thus, TNF and possibly other inflammatory cytokines in the tumor-stroma matrix likely select for breast cancer cells that stably overexpress NF-B, leading to greater cancer cell survival. Greater cell survival despite increased genomic injury may permit increased acquisition of malignant genetic alterations as well as resistance to chemoradiation therapy. (Mol Cancer Res 2008;6(1):78–88)