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Cancers of the breast, prostate, and lung commonly metastasize to the bone resulting in osteolysis, pathologic fracture, pain and significant clinical morbidity. To date, the reason for such selectivity in the site of metastasis remains largely unknown. During both normal bone remodeling and pathologic processes such as osteolytic bone metastases, growth factors and cytokines stored in the bone are released into the local environment where they have the potential to influence the behavior of neighboring cells. Insulin-like growth factor (IGF) and transforming growth factor beta (TGF-β) are two such factors. Using cDNA microarrays, we have shown that exposure of MDA-MB-231 breast cancer cells to these growth factors results in a number of changes in the gene expression profile of the cells. Specifically, TGF-β stimulates the growth of these cells at very low concentrations, while at higher concentrations the effect of this cytokine are stimulatory. Expression of the insulin-like growth factor binding protein 3 (IGFBP-3) mimics this dose dependent response, suggesting that IGFBP-3 is involved in mediating TGF-β's mitogenic effects. This action appears to be independent of IGF. To definitively determine whether the increase in IGFBP-3 is causing the proliferative changes described, we generated a number of stable cell lines in which IGFBP-3 was either overexpressed or blocked using full length IGFBP-3 cDNA and shRNA targeted against IGFBP3, respectively. When compared to the parental cell line, IGFBP-3 production was increased up to two fold in overexpressing clones, while shRNA decreased protein secretion by up to 80%. Altering IGFBP-3 production in these cells was sufficient to alter the proliferative capacity of the cells as measured using a XTT proliferation assay. Thus, our data suggests that TGF-β induced IGFBP-3 plays a key role in stimulating the growth of metastatic breast tumors invading the bone, and this may represent a target for future cancer therapies. (This research was funded by the Canadian Breast Cancer Research Initiative and a fellowship to E.G. from the Canadian Breast Cancer Foundation.)

[Proc Amer Assoc Cancer Res, Volume 47, 2006]