期刊
BREAST CANCER RESEARCH AND TREATMENT
卷 126, 期 1, 页码 15-25出版社
SPRINGER
DOI: 10.1007/s10549-010-0883-2
关键词
PDGF-D; Breast cancer; Invasion; NF-kappa B; Notch-1; Jagged-1; EMT
类别
Platelet-derived growth factor-D (PDGF-D) has been linked with several human malignancies; however, its role in breast cancer progression is not known. We found that PDGF-D expressing breast cancer cell lines MDA-MB-231 and SUM-149 are more invasive compared to cell lines with little or no expression of PDGF-D such as MDA-MB-468 and MCF-7 cells. Over-expression of PDGF-D in PDGF-D low expressing MDA-MB-468 and MCF-7 cells by cDNA transfection showed increased cell proliferation while silencing the expression of PDGF-D by siRNA in PDGF-D high expressing MDA-MB-231 and SUM-149 cells showed decreased cell proliferation and increased apoptosis. Moreover, PDGF-D over-expression was positively correlated with the expression of Notch-1 and Jagged-1, and the expression of mesenchymal markers (Vimentin and ZEB-2) with concomitant decreased expression of epithelial marker E-cadherin. Since NF-kappa B activation plays a crucial role in Notch signaling as well as in epithelial-mesenchymal transition and tumor aggressiveness, we determined the DNA binding activity of NF-kappa B and our findings are consistent showing that PDGF-D over-expression led to increased DNA binding activity of NF-kappa B while it was found to be decreased by inactivation of PDGF-D. These results were also consistent with the expression and activity of MMP-9 and VEGF, as well as invasive characteristics. Further, forced expression of Notch-1/Jagged-1 by cDNA transfection de-repressed the effects of PDGF-D silencing on NF-kappa B activity and invasion. From these results, we conclude that PDGF-D plays an important role in breast tumor aggressiveness and this process is mechanistically linked with the activation of Notch and NF-kappa B signaling.
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