The role of MEKK1-dependent gene expression in tumor progression

DESCRIPTION (provided by applicant): My career plans are in academic biomedical research. I have received broad training in the characterization of kinase signaling and function. However, a major focus of my independent research will be the identification of genetic changes mediated by signaling networks;this requires new areas of expertise in array-based genetic screens and animal models to identify potential targets for therapeutic intervention. Gary Johnson is an excellent choice as my mentor in light of his experience in training researchers and his proven ability to address important questions of signaling function in cell biology. My co-mentors Drs. Van Dyke and Perou are also committed to my training and have considerable experience in approaches and methods required in my research. The UNC Lineberger Cancer Center is home to CORE facilities that will provide support throughout the research project. Thus UNC provides an outstanding scientific environment that also includes interaction with senior faculty and participation in seminar series. The goal of this project is to define the role of MEKK1 signaling in the regulation of tumor progression. MEKK1 regulates gene expression by controlling AP-1 transcription factor activity, expression and stability. In a transgenic mouse model that develops metastatic mammary adenocarcinoma, MEKK1-deficient transgenic mice show delayed formation of metastases compared to control littermates. The hypothesis is that MEKK1 regulates tumor progression through multiple mechanisms. The proposed studies will determine the impact of MEKK1 on gene expression required for tumor progression. MEKK1-dependent genes will be identified by using gene array analysis to compare MEKK1-deficient cells to those that express MEKK1. Expression of these genes will be blocked in invasive breast carcinoma cells to verify that these genes regulate tumor functions required for metastasis. Live tumor imaging will be used to validate the function of these genes on the course of tumor cell metastasis in vivo. In addition, I will examine the role of previously identified MEKK1-dependent genes in the biology of breast tumor cells and non-tumor stroma. Relevance: The majority of cancer deaths are due to the formation of secondary tumors called metastasis. Greater understanding of metastasis-related mechanisms and genetics is necessary to develop new anti-metastasis therapies. MEKK1 is a gene that regulates tumor metastasis, and these studies will define how this occurs.