Bone and bone marrow are important sites of
metastasis formation in
breast cancer.
Extracellular matrix proteins with attachment properties are generally believed to play a key role in
tumorigenesis and
metastasis formation. We have investigated whether mammary
carcinoma cells (MDA-MB-231) can recognize constructs of the fairly bone-specific human
bone sialoprotein, which encompass the RGD sequence (EPRGD-NYR). Exogenously added
bone sialoprotein peptides with this amino acid sequence in their backbone structure, but not the more common
fibronectin-derived
GRGDS peptide, strongly inhibited
breast cancer cell adhesion to extracellular bone matrix at micromolar concentrations. Most cyclic derivatives with the EPRGDNYR sequence were more effective inhibitors of
tumor cell adhesion to bone than their linear equivalents. Furthermore, changes in the
RGD-tripeptide of the backbone structure of the constructs, removal of the NYR flanking sequence, or a different tertiary cyclic structure significantly decreased their inhibitory potencies. In addition, the RGE-analogue EPRGENYR was capable of inhibiting
breast cancer cell adhesion to bone, albeit to a lesser extent. We conclude therefore, that the inhibitory potency of the
bone sialoprotein-derived
peptides on
breast cancer cell adhesion to bone is not solely due to a properly positioned RGD-motif alone but is also determined by its flanking regions, together with the tertiary structure of the EPRGDNYR
peptide. Synthetic cyclic constructs with the EPRGDNYR sequence may, therefore, be potentially useful as antiadhesive agents for
cancer cells to bone in vivo.