Vascular endothelial growth factor receptor-3 is a
receptor tyrosine kinase that is overexpressed in some human
carcinomas, but its role in
tumorigenesis has not been fully elucidated. We examined
VEGFR-3 expression in normal, nonneoplastic and early stage malignant breast tissues and have shown that
VEGFR-3 upregulation in
breast cancer preceded
tumor cell invasion, suggesting that
VEGFR-3 may function as a survival signal. We characterized the
biological effects of
VEGFR-3 over-expression in human
breast cancer cells based on two approaches: gain of function by overexpressing
VEGFR-3 in MCF-7
breast cancer cells and loss of function by RNAi-mediated silencing of
VEGFR-3 in MCF-7-VEGFR-3 and BT474 cells.
VEGFR-3 overexpression increased cellular proliferation by 40% when MCF7-VEGFR-3 cells were compared to parental MCF7 cells, and proliferation was reduced by more than 40% when endogenous
VEGFR-3 was downregulated in BT474 cells.
VEGFR-3 overexpression promoted a three-fold increase in motility and invasion and both motility and invasion were inhibited by downregulation of
VEGFR-3. Furthermore,
VEGFR-3 overexpression promoted cellular survival under stress conditions induced by
staurosporine treatment and led to anchorage-independent growth.
VEGFR-3 overexpression dramatically increased
tumor formation in both
hormone-dependent and independent xenograft models. With
estrogen stimulation, MCF7-VEGFR-3 xenografts were ten times larger than control xenografts. Finally, downregulation of
VEGFR-3 expression in both xenograft model cell lines led to a significant reduction of
tumor growth. For the first time, we have demonstrated that
VEGFR-3 overexpression promotes
breast cancer cell proliferation, motility, survival, anchorage-independent growth and tumorogenicity in the absence of
ligand expression.