Ligand-Receptor Interactions Determine Signaling Potential and Oncogenicity of the Canonical Wnt Pathway.

摘要

The Wnt signaling pathway plays a central role in several biological processes, and ectopic activation of the pathway is linked with different pathologies, including cancer. The Wnt/beta-catenin pathway is specifically associated with stem cell maintenance and oncogenicity and requires expression of the low-density-lipoprotein receptor (LDLR)-related proteins, Lrp5 or Lrp6, for pathway activation. The work described in this thesis focuses on evaluating the functions of Lrp5 and Lrp6 in mouse mammary gland biology, and furthering our understanding of the molecular basis of signaling through these receptors in different cellular contexts.;We previously identified a critical role for Lrp5 in maintaining mammary ductal stem cell activity. Furthermore, earlier studies identified resistance to Wnt1-mediated mammary tumor formation in Lrp5 -/- mice, despite expression of Lrp6. Regardless of these striking phenotypic effects, absence of Lrp5 does not impact canonical Wnt pathway activation in response to the ligand, Wnt3a, in vitro raising the possibility that Lrp5 and Lrp6 mediate distinct functions in canonical Wnt pathway activation in the mouse mammary gland. To explain the divergent requirements for Lrp receptors by the two canonical Wnt ligands, we hypothesized that Wnt ligands activate Wnt/beta-catenin signaling by exhibiting differential requirements for Lrp5 and Lrp6. Using mouse embryonic fibroblasts as a model, we show that, consistent with our hypothesis, Wnt ligands indeed segregate into two classes - a 'Wnt1-class' that requires both Lrp5 and Lrp6 for optimal pathway activation and a 'Wnt3a-class' that is largely dependent on Lrp6 expression. Cumulatively, our studies provide evidence for existence of different Wnt-Lrp complexes in vivo, providing an explanation for unique functional roles of Lrp-dependent physiologies in the mouse mammary gland.;Finally, using an MMTV-Wnt1 transgenic mouse model, we evaluate lineage-specific Wnt signaling in tumors. Our studies reveal that ectopic Wnt signaling abolishes basal-specific restriction of Lrp5 expression and that acquisition of Lrp5 expression by luminal cells confers Wnt signaling potential and tumor stem cell properties. We propose that the implication of the Wnt signaling pathway in breast cancer, via extracellular dysregulation, makes targeting Lrp5 and Lrp6 a promising therapeutic strategy for the treatment of breast cancer.