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.
- Bone-breast cancer metastases
- Met receptor
- Tumour microenvironment
ASJC Scopus subject areas
- Cancer Research