Abstract
Vascular endothelial growth factor receptor-1/fms-related tyrosine kinase-1 (VEGFR-1/Flt-1) is a tyrosine kinase receptor that binds placental growth factor (PlGF). Flt-1 is also highly expressed in breast-cancer tissues and breast-cancer cell lines. However, the molecular mechanism by which Flt-1 promotes breast-cancer invasion and metastasis by binding to PlGF-1 is unclear. In this study, we discovered that PlGF-1 and Flt-1 played a key role in the migration and invasion of breast cancer. Flt-1 promoted the migration and chemotaxis of breast-cancer cells by binding to PlGF-1. In addition, Flt-1 was confirmed to be a direct target gene of miR-507. miR-507 up-regulation inhibited the invasion and metastasis of breast-cancer cells in vitro and in vivo. Flt-1 overexpression rescued the invasion partially caused by the ectopic expression of miR-507. miR-507 expression in breast-cancer tissues and cell lines was lower than that in adjacent non-neoplastic tissues and normal cells. Clinical analysis indicated that miR-507 was negatively correlated with tumor differentiation, lymphatic metastasis, and the expression of Flt-1 in breast cancer. Furthermore, we showed that miR-507 down-regulation was due to the hypermethylation of its promotor region. Our results indicated that miR-507 represented potential therapeutic targets in breast cancer by modulating Flt-1.
Highlights
Breast cancer is one of the most common malignant tumors among women
placental growth factor (PlGF)-1 promoted migration and invasion of breast-cancer cells, and Flt-1 was required for cell migration and invasion mediated by PlGF-1
Quantitative analysis of cell numbers revealed that the MCF-7 and MDA-MB-231 cell lines had the highest invasion rate that responded to 10 ng/mL rPlGF-1 (Figure 1B)
Summary
Breast cancer is one of the most common malignant tumors among women. More than 100 new cases per 100,000 women aged 55–69 years by 2021 are estimated [1]. The survival rate decreases from 90% for localized breast cancer to 20% for metastatic breast cancer [2]. Cancer metastasis is the toughest problem in cancer therapy. Understanding the molecular mechanisms underlying the invasion and metastasis of breast cancer may provide ways for developing novel antineoplastic therapies. Vascular endothelial growth factor receptor-1/ fms-related tyrosine kinase-1 (VEGFR-1/Flt-1) is a tyrosine kinase receptor that binds placental growth factor (PlGF). The PlGF-1 activates ERK1/2 kinases, which are associated with cellular motility in breast-cancer cells
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