Interaction between human-breast cancer metastasis and bone microenvironment through activated hepatocyte growth factor/Met and β-catenin/Wnt pathways

Sara Previdi, Paola Maroni, Emanuela Matteucci, Massimo Broggini, Paola Bendinelli, Maria Alfonsina Desiderio

Research output: Contribution to journalArticle

Abstract

To clarify the reciprocal interaction between human-breast cancer metastatic cells and bone microenvironment, we studied the influence of HGF/Met system on a proposed-prognostic marker of aggressiveness, the β-catenin/Wnt pathway. For in vitro and in vivo experiments we used 1833-bone metastatic clone, derived from human-MDA-MB231 cells. In osteolytic bone metastases and in metastatic cells, Met was expressed in nuclei and at plasma membrane, and abnormally co-localised at nuclear level with β-catenin and the tyrosine phosphorylated c-Src kinase. Thus, in 1833 cells nuclear-Met COOH-terminal fragment and β-catenin-TCF were constitutively activated, possibly by receptor and non-receptor tyrosine kinases. The activity of the gene reporter TOPFLASH (containing multiple TCF/LEF-consensus sites) was measured, as index of β-catenin functionality. In 1833 cells, human and mouse HGF increased Met and β-catenin tyrosine phosphorylation and expression in nuclear and perinuclear compartments, β-catenin nuclear translocation via Kank and TOPFLASH transactivation. Human HGF was autocrine/intracrine in bone metastasis, and mouse HGF originating from the adjacent host-bone marrow, was found inside the metastatic nuclei. Parental MDA-MB231 cell nuclei did not show functional β-catenin, for TCF-transactivating activity, and the regulation by HGF. Our study highlighted the importance of the metastasis-stroma interaction in human-breast cancer metastatisation and first identified the HGF/nuclear Met/phospho-c-Src/β-catenin-TCF/Wnt pathway as a potential-therapeutic target to delay establishment/progression of bone metastases by affecting the aggressive phenotype.

Original languageEnglish
Pages (from-to)1679-1691
Number of pages13
JournalEuropean Journal of Cancer
Volume46
Issue number9
DOIs
Publication statusPublished - Jun 2010

Keywords

  • β-Catenin
  • Bone-breast cancer metastases
  • HGF
  • Met receptor
  • Tumour microenvironment

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Fingerprint Dive into the research topics of 'Interaction between human-breast cancer metastasis and bone microenvironment through activated hepatocyte growth factor/Met and β-catenin/Wnt pathways'. Together they form a unique fingerprint.

  • Cite this