Bone sialoprotein peptides are potent inhibitors of breast cancer cell adhesion to bone.
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.
van der Pluijm
G
G
Department of Endocrinology and Metabolic Diseases, University Hospital, Leiden, the Netherlands.
Vloedgraven
H J
HJ
Ivanov
B
B
Robey
F A
FA
Grzesik
W J
WJ
Robey
P G
PG
Papapoulos
S E
SE
Lowik
C W
CW
D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D001842:Bone and Bones; D001943:Breast Neoplasms; D002417:Cattle; D002448:Cell Adhesion / Q000187:drug effects*; D002460:Cell Line; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D058574:Integrin-Binding Sialoprotein; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D012795:Sialoglycoproteins / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
C546871:IBSP protein, human; C546872:Ibsp protein, mouse; D058574:Integrin-Binding Sialoprotein; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D012795:Sialoglycoproteins