Increased expression of the mannose 6-phosphate/insulin-like growth factor-II receptor in breast cancer cells alters tumorigenic properties in vitro and in vivo

Int J Cancer. 2003 Nov 20;107(4):564-70. doi: 10.1002/ijc.11453.


The mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGF-IIR) is thought to act as a suppressor of tumor growth by binding the mitogenic peptide IGF-II and modulating its extracellular levels via degradation. This receptor has been found to be absent or nonfunctional in a high proportion of breast tumors as a result of LOH and mutation of the gene. In our study, we have examined the effect of increasing expression of M6P/IGF-IIR on breast cancer cell tumorigenicity. MDA-MB-231 breast cancer cells stably transfected with M6P/IGF-IIR cDNA exhibited not only a greatly reduced ability to form tumors but also a markedly reduced growth rate in nude mice. In vitro, increased M6P/IGF-IIR expression resulted in 2-fold reduced uptake of IGF-II and was associated with reduced cellular invasiness and motility. Cells with increased M6P/IGF-IIR expression exhibited reduced phosphorylation of IGF-I receptor and p44/42 MAPK compared to vector transfectants, or wild-type MDA-MB-231 cells. These results therefore suggest that M6P/IGF-IIR levels can modulate breast cancer cell tumorigenicity by a mechanism that may involve altered IGF-I receptor signaling.

MeSH terms

  • Animals
  • Blotting, Western
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology*
  • Cell Division
  • Cell Movement
  • Female
  • Humans
  • In Vitro Techniques
  • Insulin-Like Growth Factor II / metabolism
  • Mice
  • Mice, Nude
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / metabolism
  • Neoplasm Invasiveness
  • Phosphorylation
  • Plasmids / genetics
  • Receptor, IGF Type 1 / metabolism
  • Receptor, IGF Type 2 / metabolism*
  • Signal Transduction
  • Transfection
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism
  • Up-Regulation


  • Receptor, IGF Type 2
  • Insulin-Like Growth Factor II
  • Receptor, IGF Type 1
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases