The Wnt family of secreted proteins plays a variety of crucial roles in development and their intracellular signaling pathway is activated in many human cancers. Several Wnt proteins are implicated in the regulation of mammary gland development, and aberrant Wnt signaling can cause mammary tumors in mice. Wnt proteins are thought to act via cell surface receptors composed of proteins of the Frizzled family and either LRP5 or LRP6. However, the functions of individual receptor components, and the specificity of Wnt ligand-receptor interactions, remain unclear. The goals of this research will be to investigate the functions of individual Wnt proteins and their receptors in mammary development and tumorigenesis by studying signal activation and signal antagonism in a combination of cell culture and mouse model systems. The roles of LRP6 in mammary development and Wnt signaling will be explored, together with the specificity of Wnt-Frizzled and Wnt-LRP interactions. Methods of antagonizing Wnt signaling in vivo will be tested. Their effects on mouse mammary development, and on preventing premalignant hyperplasia, will be determined. The effects of activating oncogenic Wnt signaling in the mammary gland will be tested using an inducible expression system and the resulting changes in gene expression analyzed using DNA arrays. These experiments will elucidate mechanisms and functions of Wnt proteins in neoplasia of the mammary gland. Since aberrant Wnt expression and signaling is associated with human breast cancer, the results may be applicable to future strategies of Wnt receptor modulation as a means of therapeutic intervention.
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