Activation of Alternative Wnt Signaling Pathways in Human Mammary Gland and Breast Cancer Cells

摘要

Wnts are lipid-modified secreted glycoproteins that regulate diverse biological processes. I have shown that Wnt5a, which functions in non-canonical Wnt signaling, promoted proliferation, cell survival and network formation on endothelial cells. In new experiments, Wnt5a induced non-canonical Wnt signaling in endothelial cells, as measured by Dishevelled and ERK1/2 phosphorylation, as well as inhibited canonical Wnt signaling. Using shRNA technology to target Wnt5a expression, both endothelial cell network formation and migration were inhibited. A DNA array screening for Wnt5a-regulated genes in cultured cells identified several encoding angiogenic regulators, and Tie-2, a receptor for angiopoietins, was validated as a new target gene of non- canonical Wnt signaling in human endothelial cells. So far, non-canonical Wnt signaling had unknown functions on endothelial cell biology. Experimental findings from this project highlight the importance of non-canonical Wnt signaling on angiogenesis.