Programmed cell death 4 inhibits breast cancer cell invasion by increasing tissue inhibitor of metalloproteinases-2 expression

Breast Cancer Res Treat. 2009 Mar;114(2):203-9. doi: 10.1007/s10549-008-9993-5. Epub 2008 Apr 4.


High levels of the cyclooxygenase-2 (COX-2) protein have been associated with invasion and metastasis of breast tumors. Both prostaglandin E(2) (PGE(2)) and interleukin-8 (IL-8) have been shown to mediate the invasive activity of COX-2 in breast cancer cells. Here we expand these studies to determine how COX-2 uses PGE(2) and IL-8 to induce breast cancer cell invasion. We demonstrated that PGE(2) and IL-8 decreased the expression of the tumor suppressor protein Programmed Cell Death 4 (PDCD4). We hypothesized that suppression of PDCD4 expression is vital to the invasive activity of PGE(2) and IL-8. In MCF-7 cells overexpressing PDCD4 (MCF-7/PDCD4), PGE(2) and IL-8 failed to induce invasion, in contrast to the parental MCF-7 cells, thus indicating that PDCD4 blocks breast cancer cell invasion. MCF-7/PDCD4 cells produced higher levels of the Tissue Inhibitor of Metalloproteinases-2 (TIMP-2) than the parental cells. Silencing TIMP-2 mRNA in MCF-7/PDCD4 cells reversed the anti-invasive effects of PDCD4, allowing PGE(2) and IL-8 to induce the invasion of these cells. Here we report the novel findings that suppression of PDCD4 expression is vital for the invasive activity of COX-2 mediated by PGE(2) and IL-8, and that PDCD4 increases TIMP-2 expression to inhibit breast cancer cell invasion.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins / genetics*
  • Blotting, Western
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Dinoprostone / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Gene Expression / physiology
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Interleukin-8 / genetics
  • Interleukin-8 / metabolism
  • Neoplasm Invasiveness
  • RNA Interference / drug effects
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / pharmacology
  • RNA-Binding Proteins / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tissue Inhibitor of Metalloproteinase-2 / genetics*
  • Tissue Inhibitor of Metalloproteinase-2 / metabolism
  • Tumor Cells, Cultured


  • Apoptosis Regulatory Proteins
  • Interleukin-8
  • PDCD4 protein, human
  • RNA, Messenger
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • Tissue Inhibitor of Metalloproteinase-2
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Dinoprostone