title: Targeting Notch1 inhibits invasion and angiogenesis of human breast cancer cells via inhibition Nuclear Factor-κB signaling.
abstract: Notch-1, a type-1 transmembrane protein, plays critical roles in the pathogenesis and progression of human malignancies, including breast cancer; however, the precise mechanism by which Notch-1 causes tumor cell invasion and angiogenesis remain unclear. Nuclear factor-κB (NF-κB), interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMP) are critically involved in the processes of tumor cell invasion and metastasis, we investigated whether targeting Notch-1 could be mechanistically associated with the down-regulation of NF-κB, IL-8, VEGF, and MMP-9, resulting in the inhibition of invasion and angiogenesis of breast cancer cells. Our data showed that down-regulation of Notch-1 leads to the inactivation of NF-κB activity and inhibits the expression of its target genes, such as IL-8, VEGF and MMP-9. We also found that down-regulation of Notch-1 decreased cell invasion, and vice versa Consistent with these results, we also found that the down-regulation of Notch-1 not only decreased MMP-9 mRNA and its protein expression but also inhibited MMP-9 active form. Moreover, conditioned medium from Notch-1 siRNA-transfected breast cancer cells showed reduced levels of IL-8 and VEGF and, in turn, inhibited the tube formation of HUVECs, suggesting that down-regulation of Notch-1 leads to the inhibition of angiogenesis. Furthermore, conditioned medium from Notch-1 cDNA-transfected breast cancer cells showed increased levels of IL-8 and VEGF and, in turn, promoted the tube formation of HUVECs, suggesting that Notch-1 overexpression leads to the promotion of angiogenesis.We therefore concluded that down-regulation of Notch-1 leads to the inactivation NF-κB and its target genes (IL-8, MMP-9 and VEGF), resulting in the inhibition of invasion and angiogenesis.
authors.affiliation: Department of Radiation Therapy, Linyi Tumor Hospital Linyi, Shandong, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Breast Surgery, Linyi Tumor Hospital Linyi, Shandong, China.
authors.forename: Chuanfu
authors.initials: C
authors.lastname: Su
authors.affiliation: Department of Imaging, People's Hospital of Rizhao Rizhao, Shandong, China.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Shan
authors.affiliation: Department of Imaging, People's Hospital of Rizhao Rizhao, Shandong, China.
authors.forename: Shouxiang
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Imaging, People's Hospital of Rizhao Rizhao, Shandong, China.
authors.forename: Guifeng
authors.initials: G
authors.lastname: Ma
keywords: Breast cancer; Notch-1; angiogenesis; invasion; nuclear factor-κB (NF-κB)