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IKBKE-mediated transformation in breast carcinogenesis
Our group seeks to identify and functionally validate new kinase oncogenes that will be valuable targets for cancer therapy. IKBKE is a novel oncogene candidate identified from two unique genomic screens, a kinome-specific shRNAi screen and a myristoylated-FLAG-tagged kinase library screen. Our preliminary studies using these tools identified IKBKE to be essential for the viability of transformed MCF7 cells and also sufficient to mediate transformation in HEK cells. Additionally, compelling aCGH data demonstrates that IKBKE is amplified in many breast cancer tumors. From this evidence, I hypothesize that IKBKE plays a critical role in breast carcinogenesis. Here, I propose to firstly survey whether IKBKE behaves as an oncogene, secondly determine whether other IKK family members also facilitate transformation, and lastly elucidate the mechanism of how IKBKE mediates transformation. Following introduction of myristoylated-IKBKE into primary human mammary epithelial cells (HMECs), I will assess transformation potential via standard colony formation assays and in vivo tumorigenicity assays. I plan to identify IKBKE mutations by sequence analysis in breast cancer cell lines and screen breast tumors for IKBKE alterations. Other IKK family members including IKK alpha, IKK beta, IKK gamma and TBK1 will also be evaluated for the ability to transform cells, primarily through the use of shRNAi. Additionally, we will determine whether canonical NFkB signaling is crucial for IKBKE-mediated transformation. Because growing evidence links inflammation and malignant progression in breast cancer, I will further address whether IKBKE-induced interferon response factor-3 (IRF3) is responsible for the transforming ability of IKBKE. I anticipate that these studies will confirm IKBKE as a therapeutic target for drug development in breast cancer.
In effort to create new therapies that specifically target breast cancer cells, it is essential to identify breast cancer-promoting genetic pathways. Using powerful genomic tools, we have discovered a new molecule, IKBKE, that is involved in such a pathway. We demonstrate that a breast cancer cell line cannot survive when IKBKE levels are reduced. We also find that the introduction of IKBKE into normal cells causes them to behave like cancer cells. Futhermore, many breast tumors isolated from patients carry alterations in the IKBKE gene. Based on these findings, I hypothesize that IKBKE plays a critical role in the development of breast cancer. I propose to validate its ability to mediate breast tumor formation and define its mechanism of action. Ultimately, these studies potentially allow for IKBKE to be targeted as a treatment for breast cancer.