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UBC Theses and Dissertations

Role of notch signaling in angiogenesis and breast cancer Leong, Kevin G.

Abstract

The Notch family of transmembrane receptors consists of four members in mammals, Notchl through Notch4. Upon ligand binding, Notch receptors become activated and participate in intracellular signaling pathways that regulate cell fate decisions. Notchl-3 are expressed on numerous cell types. Because Notch4 is primarily expressed on endothelial cells, we postulated that Notch4 activation would modulate cell fate decisions in an endothelial-specific manner. Angiogenesis, the sprouting of endothelial cells from pre-existing microvessels, requires modulation of the endothelial cell phenotype. We have identified a role for Notch4 activation in the regulation of angiogenesis. Expression of activated Notch4 inhibits endothelial sprouting in vitro and angiogenesis in vivo. Activated Notch4 does not inhibit endothelial cell migration through the extracellular matrix protein fibrinogen, whereas migration through collagen is inhibited. Activated Notch4 increases endothelial cell adhesion to collagen by modulating the affinity state of cell-surface collagen receptors belonging to the pi integrin family. Specifically, activated Notch4 converts pi integrin from an inactive, non-ligand-binding state to an active, high-affinity conformation. Our findings suggest that Notch4 activation in endothelial cells inhibits angiogenesis in part by promoting pi integrin-mediated adhesion to the underlying matrix. Although Notch signaling regulates normal cellular processes, increasing evidence suggests a role for aberrant Notch signaling in cellular transformation. During tumor progression, epithelial tumor cells often acquire a mesenchymal phenotype through epithelial-tomesenchymal transition (EMT), a process that promotes invasion and dissemination of cancer cells. In human breast cancer, EMT directly correlates with downregulated expression of the adherens junction protein epithelial (E)-cadherin. Given that Notch pathway elements are expressed at sites of epithelial-mesenchymal cell-cell interactions during embryogenesis and within primary human breast tumors, we investigated whether Notch signaling would modulate E-cadherin expression in human breast cells. Our studies identify activated Notch signaling as a novel mechanism for the downregulation of E-cadherin expression in normal human breast epithelial cells. In human breast tumor xenografts lacking E-cadherin expression, we show that a soluble inhibitor of Notch signaling attenuates E-cadherin promoter methylation and induces Ecadherin re-expression. This re-induction of E-cadherin in turn inhibits p-catenin nuclear accumulation, resulting in a marked reduction in breast tumor growth and metastasis.

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