Cytokine Overexpression and Constitutive NFκB in Cancer

The NF?B family of transcription factors, central mediators of immune responses, are also involved in oncogenesis. Loss of regulation of the normally latent NF?B contributes importantly to the deregulated growth, resistance to apoptosis and propensity to metastasize observed in many cancers. Thus, pathways for activation of NF?B are promising targets for new agents that may help to prevent or treat cancer. We find that the abnormal secretion of multiple cytokines that activate NF?B by binding to cell-surface receptors is one of the major causes of constitutive NF?B activity in cancer. A novel finding is that the latent form of TGF?, secreted by some of these cells, can actaivate NF?B. To understand the basis of this abnormal cytokine secretion, we are using forward genetic methods to identify specific causative mutations in cancer cells.