Breast cancer is a diverse malignancy; understanding the molecular mechanisms driving tumor progression will facilitate development of targeted therapies. For example, tamoxifen, an anti-estrogen agent, used for treating estrogen receptor (ER)-positive breast tumors, and trastuzumab, a monoclonal antibody targeting HER2-overexpressing tumors, have benefitted specific subsets of breast cancer patients. However, the enormous variation in breast cancer initiation and growth complicate biological approaches to this malignancy and challenge the effectiveness of current therapies. Elucidation of novel, targetable signaling pathways in breast cancers would provide means of addressing current deficiencies in the treatment of the disease. The Wnt signaling pathway is involved in various differentiation events during embryonic development and can lead to tumor formation when aberrantly activated. Aberrant Wnt activation is found in 40-60% of breast cancers. However, because mutations in the classical intracellular components of the Wnt signaling pathway are rare, the underlying cause of this aberrant activation remains elusive and may involve dysregulation of upstream elements. In this thesis, we found that overexpression of LRP6, a Wnt signaling co-receptor, plays a crucial role in the pathogenesis of a subtype of human breast tumor. LRP6 was increased more frequently in ER or HER2-negative or triple-negative breast tumors that are either harder to treat or more likely to recur. We further demonstrated that suppression of LRP6 expression and function significantly inhibits Wnt signaling and breast tumor growth in vitro and in vivo. Mesd (mesoderm development) was previously identified as a specialized chaperone of LRP5/6. Using NMR structural and molecular tools, we first showed that the core chaperone domain of Mesd is required for the proper folding of LRP5/6, while its C-terminal escort domain ensures a safe trafficking of LRP5/6 from the ER to Golgi by preventing premature ligand binding. With the goal of developing ...