Programmed cell death 4 inhibits leptin-induced breast cancer cell invasion

Oncol Rep. 2012 Mar;27(3):861-6. doi: 10.3892/or.2011.1600. Epub 2011 Dec 21.


Obesity is a significant risk factor for post-menopausal women to develop and die from breast cancer. Leptin, an adipokine is produced in high levels in obese individuals, and its receptor is overexpressed in breast tumors and lymph node metastases. Previously, we demonstrated that leptin stimulates breast cancer cell invasion, which is correlated with breast cancer metastasis. Programmed cell death 4 (PDCD4) has been shown to block cancer cell invasion. However, whether PDCD4 blocks leptin-induced breast cancer cell invasion is not known. Here, we report the novel findings that leptin failed to induce invasion in MCF-7 breast cancer cells overexpressing PDCD4 (MCF-7/PDCD4). Tissue inhibitor of metalloproteinase-2 (TIMP-2) was essential to the anti-invasive effect of PDCD4, as leptin stimulated the invasion of MCF-7/PDCD4 cells pretreated with TIMP-2 siRNA. Furthermore, TIMP-2 knockdown allowed leptin to augment phosphorylation of extracellular signal-regulated kinases 1,2 and signal transducer and activator of transcription 3, but not that of Jun N-terminal kinases. These data indicate that PDCD4 utilizes TIMP-2 to exert its anti-invasive effect by suppressing leptin-induced activation of extracellular signal-regulated kinases 1,2 and signal transducer and activator of transcription 3. Novel therapeutic strategies aiming at enhancing PDCD4 expression in breast tumors may be able to stop obesity-related breast tumor progression and prolong the life of patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins / biosynthesis*
  • Apoptosis Regulatory Proteins / genetics
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Female
  • Gene Knockdown Techniques / methods
  • Humans
  • JNK Mitogen-Activated Protein Kinases / genetics
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Leptin / antagonists & inhibitors*
  • Leptin / metabolism
  • Leptin / pharmacology
  • MAP Kinase Signaling System
  • Neoplasm Invasiveness
  • Phosphorylation / genetics
  • RNA, Small Interfering / genetics
  • RNA-Binding Proteins / biosynthesis*
  • RNA-Binding Proteins / genetics
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • Tissue Inhibitor of Metalloproteinase-2 / genetics
  • Tissue Inhibitor of Metalloproteinase-2 / metabolism
  • Transfection


  • Apoptosis Regulatory Proteins
  • Leptin
  • PDCD4 protein, human
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • TIMP2 protein, human
  • Tissue Inhibitor of Metalloproteinase-2
  • JNK Mitogen-Activated Protein Kinases