Vascular endothelial growth factor receptor-1 (VEGFR-1 or Flt-1), a
tyrosine kinase receptor, is highly expressed in
breast cancer tissues, but near absent in normal breast tissue. While
VEGFR-1 expression is associated with poor prognosis of women with
breast cancer, it is not clear whether it is involved in the aggressiveness of
breast cancer. Thus, the present study examined whether
VEGFR-1 activation is associated with the invasiveness of
breast cancer. We reported that
VEGFR-1 was detected in 60.6% of invasive
breast carcinoma tissue sections. In addition,
VEGFR-1 expression positively correlated with lymph node-positive
tumor status, low expression level of membranous
E-cadherin, and high expression levels of
N-cadherin and Snail. We found that PlGF-mediated
VEGFR-1 activation promoted migration and invasion in MCF-7 (
luminal) cells and led to morphologic and molecular changes of epithelial-mesenchymal transition (EMT). This was blocked by the down-regulation of
VEGFR-1. Conversely, down-regulation of
VEGFR-1 in MDA-MB-231 (post-EMT) cells resulted in morphologic and molecular changes similar to mesenchymal-epithelial transition (MET), and exogenous PlGF could not reverse these changes. Moreover,
VEGFR-1 activation led to an increase in nuclear translocation of Snail. Finally, MDA-MB-231 cells expressing
shRNA against
VEGFR-1 significantly decreased the
tumor growth and
metastasis capacity in a xenograft model. Histological examination of VEGFR-1/
shRNA-expressing
tumor xenografts showed up-regulation of
E-cadherin and down-regulation of
N-cadherin and Snail. These findings suggest that
VEGFR-1 may promote
breast cancer progression and
metastasis, and
therapies that target
VEGFR-1 may be beneficial in the treatment of
breast cancer patients.