Platelet-derived Growth factor-D Contributes to Aggressiveness of Breast Cancer Cells by Up-Regulating Notch and NF-κB Signaling Pathways

Breast Cancer Res Treat. 2011 Feb;126(1):15-25. doi: 10.1007/s10549-010-0883-2. Epub 2010 Apr 9.


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-κB 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-κB and our findings are consistent showing that PDGF-D over-expression led to increased DNA binding activity of NF-κB 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-κB 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-κB signaling.

Publication types

  • Retracted Publication

MeSH terms

  • Apoptosis
  • Blotting, Western
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology*
  • Calcium-Binding Proteins
  • Cell Adhesion
  • Cell Movement
  • Cell Proliferation
  • Colony-Forming Units Assay
  • Electrophoretic Mobility Shift Assay
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Jagged-1 Protein
  • Luciferases / metabolism
  • Lymphokines / antagonists & inhibitors
  • Lymphokines / genetics
  • Lymphokines / metabolism*
  • Membrane Proteins
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Neoplasm Invasiveness
  • Platelet-Derived Growth Factor / antagonists & inhibitors
  • Platelet-Derived Growth Factor / genetics
  • Platelet-Derived Growth Factor / metabolism*
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Serrate-Jagged Proteins
  • Signal Transduction*
  • Tumor Cells, Cultured


  • Calcium-Binding Proteins
  • Intercellular Signaling Peptides and Proteins
  • JAG1 protein, human
  • Jagged-1 Protein
  • Lymphokines
  • Membrane Proteins
  • NF-kappa B
  • NOTCH1 protein, human
  • PDGFD protein, human
  • Platelet-Derived Growth Factor
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptor, Notch1
  • Serrate-Jagged Proteins
  • Luciferases