WNT SIGNALING IN TISSUE BIOLOGY AND CANCER

The Wnt family of secreted signaling factors is a major group of developmental regulators whose signaling mechanism is frequently activated in human cancer. Wnt proteins fulfill crucial functions in specification and patterning of a wide variety of tissues during mammalian development, and in tissue homeostasis in the adult. At the cellular level, Wnt proteins can regulate cell fate determination, proliferation, apoptosis, differentiation, adhesion, and migration. Recent evidence also implicates Wnt signaling in regulating the self-renewal of pluripotent cells, suggesting that it may have a important role to play in stem cell therapeutics.

In the well characterized Wnt/beta-catenin or 'canonical' Wnt signaling pathway, Wnt ligands bind to receptors composed of a Frizzled protein and one of the LDL receptor-related proteins LRP5 or LRP6. Downstream signaling leads to stabilization and nuclear accumulation of beta-catenin protein which, in combination with TCF factors, modulates the expression of specific target genes. Activating mutations in the canonical Wnt pathway are found in a wide spectrum of human cancers, where they play an initiating role. In other cancers, such as breast cancer, the pathway is implicated by frequent accumulation of beta-catenin. While many Wnt proteins act via the canonical pathway, there are also 'non-canonical' Wnt signaling mechanisms that do not involve beta-catenin. Such signaling is less well characterized but is thought to play critical roles in morphogenesis by mediating planar cell polarity and cell movements in the embryo. Altered non-canonical Wnt signaling is also associated with human cancer, particularly with malignant cell invasion.

Research in the laboratory centers on basic mechanisms of Wnt signaling, and understanding how altered Wnt signaling contributes to cancer. The role of stem-like cells in tumorigenesis is of particular interest and a long-term goal is to develop novel strategies for cancer prevention and treatment. Recently we have focused on the determinants of Wnt signaling specificity (canonical versus non-canonical), the role of individual receptor components in signal transduction, and the role of Dishevelled (Dvl) proteins in Wnt signaling pathways. We have found that phosphorylation of Dvl is a manifestation of non-canonical signaling but is also induced by Wnts that activate the canonical pathway. This implies that many Wnts consistently activate both signaling mechanisms in the same cells. Dvl phosphorylation now provides a robust biochemical assay for further investigation of non-canonical Wnt signaling. Our in vivo studies focus on mouse models of breast cancer. We are manipulating specific aspects of Wnt signaling in the mammary gland to elucidate the functions of these pathways in normal development and cancer.

E-mail: amcbrown@med.cornell.edu