The epithelial adhesion molecule E-cadherin is an established invasion suppressor, and its expression is downregulated during tumor metastatic progression. The expression of E-cadherin transcriptional repressors by tumor cells represents a prominent strategy for downregulating E-cadherin during tumor metastatic progression. In particular, the E-cadherin transcriptional repressor Snail is a prognostic marker for metastatic ductal breast carcinoma, being expressed in node-positive, but not in low grade, node-negative specimens. Despite the established importance of Snail for breast tumor growth and recurrence, few studies have defined the factors that regulate Snail expression in breast cancer. In the current studies, we define a non-angiogenic, autocrine function for VEGF in the regulation of Snail expression. The transfection of breast carcinoma cells with a VEGF-A-expressing plasmid increases Snail expression, resulting in reduced E-cadherin protein levels. Conversely, inhibiting endogenous VEGF activity in these breast carcinoma cells reduces Snail expression. We provide evidence that the ability of VEGF to induce Snail is dependent on Neuropilin-1, a non-tyrosine kinase VEGF receptor expressed in breast tumors. Previous studies have established a definitive role for VEGF in angiogenesis. The current studies indicate that VEGF may also impact tumor progression in an autocrine fashion by driving the expression of Snail, a breast tumor progression factor.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA