Project 2 focuses on the interaction of protein kinase CK2 (casein kinase II) and the Wnt signaling pathway with carcinogens in the process of mammary tumorigenesis. In the prior granting period, we demonstrated that the serine-threonine kinases CK2 and GSK3(3 have opposing effects on Wnt signaling, and that CK2 and a kinase inactive (Kl) form of GSK3(3 can promote mammary tumorigenesis in vivo that is associated with activated Wnt signaling. With our P01 collaborators, we established a model of carcinogen-induced mammary tumorigenesis in FVB mice, and found upregulation of Wnt signaling, CK2, the aryl hydrocarbon receptor, and NF-KB in the tumors. Thus, activation of CK2 and inhibition of GSK33 are demonstrated to have the potential to contribute to mammary tumorigenesis and to the regulation of multiple signaling pathways. The central hypothesis of this renewal is that CK2 and Wnt signaling are constitutivelv activated by genetic and epiqenetic events in breast cancer and are regulators of epithelial to mesenchymal transition (EMT). leading to tumor invasion and to metastasis. This hypothesis will be tested through three specific aims:
Aim 1. We will study the interaction of a prototypical polycyclic aromatic hydrocarbon, DMBA with CK2 and Wnt signaling in vivo, using MMTV-CK2a transgenic mice and LEF-EGFP Wnt reporter transgenic mice.
Aim 2. One of the features of tumor progression is the loss of normal epithelial morphology and alteration in cell adhesion molecules, through the process of EMT. In this aim we will explore the mechanism by which CK2 and NF-KB collaborate to promote the EMT phenotype, and determine whether antagonizing CK2 can reverse the invasive and/or metastastatic phenotype of tumor cells.
Aim 3. Here we will investigate the mechanism of upregulation of CK2 after exposure to carcinogens. The kinetics, level of regulation, and requirement for AhR, NF-KB, and Wnt signaling in the process of upregulation of CK2 will be assessed. Signficance: Identifying collaborating events in the process of tumor progression to the EMT-like phenotype is of tremendous translational potential for preventing or curing invasive and/or metastatic cancer. If a kinase is an important contributor in model systems, with evidence that this may also be the case in human breast cancer, it provides a potential target for therapeutic intervention.
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