Role of insulin-like growth factor binding proteins (IGFBPs) in breast cancer proliferation and metastasis.

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. The bone is a rich source of many chemokines and growth factors, including: insulin-like growth factor (IGF) I and II, transforming growth factor-beta (TGF-beta), interleukins, and tumour necrosis factor-alpha (TNF-alpha). We propose that exposure of breast cancer cells to the bone microenvironment results in alterations in gene expression that favour the growth and proliferation of tumour cells in the bone. To investigate this hypothesis, MDA-MB-231 breast carcinoma cells were exposed to bone-derived conditioned media (BDCM) generated by culturing fetal rat calvaria for 24 h under serum free conditions. Using cDNA microarray technology, we have identified the insulin-like growth factor family of binding proteins (IGFBPs) as genes whose expression profiles are consistently and significantly altered with exposure to this simulated bone environment in vitro, when compared to untreated controls. Our data suggests that the upregulation of IGFBP-3 seen with exposure to the bone microenvironment is directly linked to an increase in TGF-beta mediated cell proliferation. Furthermore, this process appears to be functioning through an IGF-independent mechanism.