IKK and (Beta) - Catenin in Breast Cancer

Abstract : The wnt signaling pathway activates oncogene, beta-catenin. It associates with an APC, GSK-3b and axin complex which targets it for phosphorylation and ubiquitin-mediated degradation. NFkB transcription factor is associated with inhibitory IkBa. lts activation occurs through targeted degradation of IkBa by IkB kinase complex (IKK) .The same phosphorylation consensus sequence on IkBa and beta-catenin target them for ubiquitination. Since the degradation pathway is similar, similar kinases may be involved. It is shown that IKKb plays a major role in NFkB activation. On the other hand, IKKa knockout mice have a phenotype characterized by hyperproliferation of basal cells. This is characteristic of elevated beta-catenin signaling in epithelial stem cells. Thus IKKa may have a role in the differentiation of breast epidermal tissue by modulating the activity of beta- catenin. Cytokine tumor necrosis factor(TNFa) and EDAR activate the IKK complex. EDAR(ectodysplasin receptor) is a member of the TNF family involved in differentiation of ectodermal tissues such as the breast and represents an appropriate model to study cytokine regulation of beta-catenin in breast tissue development. Our results have shown that the effects of beta-catenin signaling is mediated by IKK and independent of APC. This project further characterizes the interaction between cytokines and beta-catenin and investigates the role that cytokines may play in breast cancer.