Parathyroid hormone-related peptide regulates matrix metalloproteinase-13 gene expression in bone metastatic breast cancer cells

Soichiro Ibaragi, Tsuyoshi Shimo, Masahiro Iwamoto, Nur Mohammad Monsur Hassan, Shinichi Kodama, Sachiko Isowa, Akira Sasaki

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)


Background: Breast cancer (BC) cells often metastasize to bone where they express large amounts of parathyroid hormone-related protein (PTHrP). In this study, we investigated the possibility that PTHrP may have roles in breast cancer bone metastasis independently of, or in addition to, its roles in osteoclastic function. Materials and Methods: A mouse model of bone metastasis was prepared by inoculating mice with suspensions of the human BC cell line MDA-MB231 tumor cells via the left cardiac ventricle. Matrix metalloproteinase-13 (MMP-13) expression in the bone microenvironment was examined by Western blot and Realtime RT-PCR (RT-PCR) analysis, as well as by confocal microscopy. Results: The invading MDA-MB-231 cells contained conspicuous amounts of both PTHrP and MMP-13, an important matrix-degrading enzyme; and treatment of the cells in culture with exogenous PTHrP markedly stimulated MMP13 gene expression. Analysis of signaling mechanisms showed that PTHrP treatment led to rapid increases in the levels of phosphorylated protein kinase C (PKCα) and extracellular signal-regulated kinase (ERK1/2). Pharmacologic inhibition of ERK1/2 and PKC as well as of PKA activities counteracted the PTHrP-dependent stimulation of MMP13 expression. Indeed, pharmacologic activation of PKA or PKC was sufficient for stimulation of MMP13 expression. Conclusion: Consistent with these findings, the inhibition of PKC prevented PTHrP-induced activation of ERK1/2, whereas 12-O-tetradecanoylphorbol- 13-acetate (TPA), a stimulator of PKC, up-regulated the PTHrP-induced activation of ERK1/2. Taken together, our data indicate that the MDA-MB-231 breast cancer cells may carry out bone destruction and favor their own metastatic behavior by producing MMP-13. Given that the cells expressed PTHrP and that this factor stimulated MMP-13 expression, metastatic bone destruction may result from a PTHrP autocrine loop involving a PKC-ERK1/2 signaling pathway.

Original languageEnglish
Pages (from-to)5029-5036
Number of pages8
JournalAnticancer research
Issue number12
Publication statusPublished - Dec 2010


  • Bone metastases
  • Breast cancer
  • ERK
  • Extracellular signalregulated kinase
  • MAPK
  • MMP13
  • Mitogen-activated protein kinase
  • PKC
  • PTHrP
  • Parathyroid hormone-related peptide
  • Protein kinase C

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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