NF-κB Regulates Radioresistance Mediated By β1-Integrin in Three-Dimensional Culture of Breast Cancer Cells

beta 1-integrin induction enhances breast cancer cell survival after exposure to ionizing radiation (IR), but the mechanisms of this effect remain unclear. Although NF-kappa B initiates prosurvival signaling pathways post-IR, the molecular function of NF-kappa B with other key elements in radioresistance, particularly with respect to extracellular matrix-induced signaling, is not known. We discovered a typical NF-kappa B-binding site in the beta 1-integrin promoter region, indicating a possible regulatory role for NF-kappa B. Using three-dimensional laminin-rich extracellular matrix (3D lrECM) culture, we show that NF-kappa B is required for beta 1-integrin transactivation in T4-2 breast cancer cells post-IR. Inhibition of NF-kappa B reduced clonogenic survival and induced apoptosis and cytostasis in formed tumor colonies. In addition, T4-2 tumors with inhibition of NF-kappa B activity exhibit decreased growth in athymic mice, which was further reduced by IR with downregulated beta 1-integrin expression. Direct interactions between beta 1-integrin and NF-kappa B p65 were induced in nonmalignant breast epithelial cells, but not in malignant cells, indicating context-specific regulation. As beta 1-integrin also activates NF-kappa B, our findings reveal a novel forward feedback pathway that could be targeted to enhance therapy. (c) 2013 AACR.