Grant: Operating Grant - Priority Announcement: Breast Cancer

We have been investigating the molecular basis of a fundamental process called "Epithelial to Mesenchymal Transition" ( EMT), which converts normal and cancer cells into highly migratory and invasive cells, leading to the spread of tumor cells from the primary tumor to distant organs, a process called metastasis. EMT has now been shown to represent a very imoportant process for tumor dissemination, including the dissemination of "cancer stem cells", a subpopulation of cells that sustain tumor growth, and are resistant to chemotherapy and radiation. Targeting this process is therefore essential for effective therapy of cancer. We have been studying a protein called Integrin Linked Kinase (ILK), which we and others have shown to play an essential role in the EMT process. The ILK protein has now been established to be overexpressed in many types of human cancers, with high levels predicting poor patient prognosis. We have determined that ILK modulates several cellular signaling mechanisms involved in EMT. In this application we propose to extend our findings over the last 4 years to precisely determine how ILK controls these mechanisms in the process of EMT as well tumor cell proliferation, key contributors of aggressive tumor behavior. We have developed several cell based and mouse model systems to determine the role of ILK in controling other key cellular signaling pathways known to contribute to oncogenesis. This in depth understanding will allow us to develop more precise therapeutic approaches that will target not only ILK but its associated protein complexes and pathways for the treatmment of advanced cancer.