Genomic damage triggers a signal transduction network that modulates gene expression and protein stability to repair DNA and influence cell survival. Inhibition of the DNA damage response protein PARP-1 is the subject of ongoing preclinical and clinical investigations in breast cancer, where DNA damage activates protective signaling networks that are transmitted through the extracellular matrix by the transmembrane protein β1-integrin. β1-integrin influences gene expression by modulating activity of the transcription factor NF-κB, yet the mechanism by which DNA damage activates β1-integrin is unknown. Here we demonstrate that breast cancer cells are enriched in PARP-1, and that PARP-1 activity is required for signaling through the tumor microenvironment in response to ionizing radiation. Moreover, PARP-1 and β1-integrin cooperatively regulate viability and growth of breast cancer cells propagated in three dimensional laminin-rich extracellular matrix (3D lrECM) cultures. Finally, we show that PARP-1 interacts with both β1-integrin and NF-κB in response to genotoxic stress to link signaling through the extracellular matrix to changes in gene expression. The data are consistent with a model whereby PARP-1 inhibition sensitizes cancer cells to the cytotoxic effects of DNA damage by coordinated disruption of both tumor microenvironment- and NF-κB-signaling pathways.
Keywords: Breast cancer, tumor microenvironment, PARP-1, β1-integrin, NF-κB