P3-01-06: NF-kB Inhibition Promotes Radiosensitivity of Breast Cancer Cells in Three-Dimensional Culture through Abating b1-Integrin Expression.

Abstract

Abstract Therapy-associated tumor resistance, giving rise to recurrence and mortality, is a critical issue in cancer therapy. The molecular mechanisms causing tumor resistnace to the therapeutic radiation remain elusive. Nuclear factor-KB (NF-KB), a stress-sensitive heterodimeric transcription factor in the regulation of the stress-responsive genes, has been shown to initiate prosurvival signaling pathways. The cooperative function of NF-KB with other key stress elements in radioresistance remains to be elucidated. We have previously reported that induction of α5β1-integrin is associated with the enhanced cell survival of breast cancer cells after exposure to high dose IR (ionizing radiation). Because a typical NF-KB binding site was located in human β1-integrin promoter region, β1-integrin-mediated resistance to radiation may be regulated by NF-KB. The aim of the present study was to reveal a connection between NF-KB and β1-integrin pathways in radioprotection of malignant T4-2 mammary epithelial cells in 3D ***lrECM (three-dimensional laminin-rich extracellular matrix). We show that the elevated NF-KB activity was correlated with enhanced clonogenic survival, and increased NF-KB heterodimer p50/p65 levels were associated with an increase in total and phosphorylated (Thr 788/789) β1-integrins. Inhibition of NF-KB activation significantly reduced clonogenic survival with the inhibition of β1-integrin. These results indicate that NF-KB-mediated induction of β1-integrin is associated with an increased radiation resistance. Treatment of T4-2 colonies, formed at day 4, with NF-KB activation inhibitor in 3D lrECM before exposure to IR (4-Gy X-ray) resulted in a reduction of the size of colonies. The surviving colonies were associated with a decrease in proliferation and increase in apoptosis, indicating a decrease of resistance to IR. Together, these results provide the first evidence that NF-KB-mediated β1-integrin expression is responsible for tumor radioresistance. The NF-KB/β1-integrin pathway may serve as an efficient drug target to re-sensitize radioresistant tumor cells. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-01-06.