BMP-6 inhibits MMP-9 expression by regulating heme oxygenase-1 in MCF-7 breast cancer cells

J Cancer Res Clin Oncol. 2011 Jun;137(6):985-95. doi: 10.1007/s00432-010-0963-z. Epub 2010 Dec 7.


Purpose: BMP-6, which belongs to the TGF-β superfamily, is a multifunctional molecule with distinct abilities in embryogenesis and organogenesis. Our recent research has implied that BMP-6 may suppress breast cancer metastasis. In the present study, we extended to elucidate the molecular mechanism by which BMP-6 exerts its anti-tumorigenic effect.

Methods: The Boyden chamber assay was used to examine the ability of BMP-6 and HO-1 in MCF-7 malignant progress. RT-PCR, western blot, luciferase assay, and quantitative CHIP were used to determine the potential mechanism and signaling pathways by which BMP-6 and HO-1 function as anti-metastatic factors in MCF-7 cells.

Results: The Boyden chamber assay showed that BMP-6 inhibited the migration and invasion of MCF-7 cells, which effect was significantly deprived by knockdown of HO-1. We further demonstrated that BMP-6 treatment resulted in an activation of HO-1 transcription through the recruitment of Smad1/5 to the Smad-responsive element on its promoter. In addition, BMP-6-induced up-regulation of HO-1 exhibited an inhibitory effect on MMP-9 secretion in a paracrine action in MCF-7 cells. Overexpression of BMP-6 and HO-1 synergistically suppressed MMP-9 transcription, which effect was specifically mediated via the MAPK/p38/AP-1 signaling. However, blockade of HO-1 using ZnPPIX totally abolished BMP-6-regulated MMP-9 activation in MCF-7 cells.

Conclusions: These observations suggest a novel role of BMP-6/HO-1 cascade to relieve breast cancer metastasis by regulating the secretion of growth factors in tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Morphogenetic Protein 6 / physiology*
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Female
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / physiology*
  • Humans
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase Inhibitors*
  • Neoplasm Metastasis / prevention & control
  • Signal Transduction
  • Smad Proteins / physiology
  • Transcription Factor AP-1 / physiology
  • p38 Mitogen-Activated Protein Kinases / physiology


  • BMP6 protein, human
  • Bone Morphogenetic Protein 6
  • Matrix Metalloproteinase Inhibitors
  • Smad Proteins
  • Transcription Factor AP-1
  • HMOX1 protein, human
  • Heme Oxygenase-1
  • p38 Mitogen-Activated Protein Kinases
  • Matrix Metalloproteinase 9