ARTICLE ABSTRACTAlterations in nuclear factor kappaB (NFκB) signaling have been related with several diseases and importantly also with cancer. Different animal models with increased or diminished NFκB signaling have shown that NFκB subunits and their regulators are relevant to the pathophysiology of different organs and tissues. In particular, both the deletion of the regulatory subunit β of the kinase of the inhibitor of NFκB (IKKβ) and its overexpression in epidermis lead to the development of skin inflammatory diseases not associated with tumoral lesions. In this work, we have studied the consequences of IKKβ overexpression in other organs and tissues. We found that elevated IKKβ levels led to altered development and functionality of exocrine glands (i.e., mammary glands) in transgenic female mice. In oral epithelia, increased IKKβ expression produced lichenoid inflammation with abundant granulocytes, macrophages, and B cells, among other inflammatory cells. This inflammatory phenotype was associated with high incidence of tumoral lesions in oral epithelia, contrary to what was found in skin. Moreover, IKKβ also increased the malignant progression of both spontaneous and experimentally induced oral tumors. These results highlight the importance of IKKβ in epithelial and glandular homeostasis as well as in oral tumorigenesis and open the possibility that IKKβ activity might be implicated in the development of oral cancer in humans. Mol Cancer Res; 9(10); 1329–38. ©2011 AACR.