This proposal explores how the beta-catenin pathway regulates growth control and tissue modeling during embryonic skin formation, with objectives to manage this pathway in cancer. This pathway is frequently altered in malignancies. Normally beta-catenin binds to E-cadherin, a cell adhesion molecule lost in mammary tumors and to APC (adenomatous polyposis coli), a tumor suppressor lost in colon cancer. APC targets beta-catenin for degradation. Wnt signaling or mutations in the pathway block APC from binding beta-catenin and lead to the accumulation of beta-catenin in the nucleus. Here it associates with LEFs/TCFs to control transcription of c-myc, cyclin D1 other cell proliferation regulatory molecules as well as metalloproteinases involved in tissue modeling. When the molecular pathway is intact, growth control is kept in check. Alterations in the pathway lead to loss of growth control, changes in cell morphology and metastasis. A powerful approach to understanding and managing the pathogenesis of the beta-catenin pathway in cancer is to examine how it is regulated and functions in development. Here we take this approach to learn its physiological function in the skin new growth model. The growth of skin appendages is an established model system for the study of rapid new growth. Beta-catenin is expressed in these regions. Preliminary data showed that beta-catenin expression levels are low in apteric and scale producing regions and higher in feather producing regions. Over-expression of beta-catenin induces new feather growth from apteric and scale forming regions and abnormal growth in feather producing regions, suggesting that higher beta-catenin expression levels lead to the formation of more complex structures. Skin sections showed multiple areas of activated epidermal thickening with high cell proliferation activity preceding new feather growth. We hypothesize that the beta-catenin pathway plays pivotal roles in the control of new growth through interactions with Lef-1 and that subsequent transcriptional activation leads to changes at the level of cell proliferation and tissue modeling. We will study the function of beta-catenin, LEFs/TcFs and cadherin in this new growth using retroviral mediated gene delivery of mutated forms, missing domain-specific functions. The morphological and molecular phenotypes will be assayed in the scale - feather new growth assay. We will also study the cellular mechanisms through which this pathway regulates growth control focusing on cell proliferation and migration and tissue modeling. Knowledge gained from these studies will be useful in the diagnosis and treatment of many forms of cancer.
