NF-?B regulates radioresistance mediated by ?1-integrin in three-dimensional culture of breast cancer cells.

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

SUBMITTER: Ahmed KM 

PROVIDER: S-EPMC3698967 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature