bone sialoprotein; breast cancer; microcalcifications
Abstract :
[en] Microcalcifications are often associated with human mammary lesions, particularly with breast carcinomas. To date, the molecular mechanism that leads to the deposition of hydroxyapatite in the mammary tissue has not been elucidated. Bone sialoprotein (BSP) is a glycoprotein the expression of which coincides with the appearance of the first hydroxyapatite crystals during bone development. In this study, we report the observation that BSP, a bone matrix protein, is expressed in human mammary cancer cells. Using an immunoperoxidase technique, we studied the expression of BSP in 79 breast lesions, including 28 benign and 51 malignant specimens. Two polyclonal antibodies, one directed against intact human BSP and the other against a synthetic peptide of BSP (residues 277-294), were used and gave identical results. Normal mammary glands expressed undetectable or barely detectable amounts of BSP, and the majority of the benign lesions examined were generally unstained (0) or weakly stained (1+). Most of the breast carcinoma specimens (around 87%) showed a significant increase (P = 0.0001) in BSP expression. Breast carcinomas with microcalcifications had the highest immunoreactivity (2+ or 3+) to BSP antibodies. This is the first demonstration that BSP expression is significantly increased in breast cancer. Expression of BSP by breast cancer cells could play a major role in the deposition of microcalcifications and in the preferred bone homing of breast cancer cells.
Snyder, R., and Rosen, P. Radiography of breast specimens. Cancer (Phila.), 28: 1608, 1971.
Ahmed, A. Calcification in human breast carcinomas: ultrastructural observations. J. Pathol., 117: 247-251, 1975.
Frappart, L., Boudeulle, M., Boumendil, J., Lin, H.C., et al. Structure and composition of microcalcifications in benign and malignant lesions of the breast. Hum. Pathol., 15: 880-889, 1984.
Posner, A. The mineral of bone. Clin. Orthop. Relat. Res., 200: 87-99, 1985.
Gehron Robey, P., Bianco, P., and Termine, J. The cellular biology and molecular biochemistry of bone formation. In: F.I. Coe and M.J. Favus (eds.), Disorders of Bone and Mineral Metabolism, pp. 241-263. New York: Raven Press, 1992.
Franzen, A., and Heinegard, D. Isolation and characterization of two sialoproteins present in bone calcified matrix. Biochem. J., 232: 715-724, 1985.
Oldberg, A., Franzen, A., and Heinegard, D. The primary structure of a cell-binding bone sialoprotein. J. Biol. Chem., 263: 19430-19432, 1988.
Bianco, P., Fisher, L., and Young, M. Expression of bone sialoprotein in human developing bone as revealed by immunostaining and in situ hybridization. J. Bone Miner. Res., 4 (Suppl.): S246, 1989.
Bianco, P., Fisher, L.W., Young, M.F., Termine, J.D., and Robey, P.G. Expression of bone sialoprotein (BSP) in developing human tissues. Calcif. Tissue Int., 49: 421-426, 1991.
Wewer, U., Albrechtsen, R., Fisher, L., Young, M., and Termine, J. Osteonectin/SPARC/BM40 in human decidua and carcinoma, tissues caracterized by de novo formation of basement membrane. Am. J. Pathol., 132: 345-355, 1988.
Craig, A., Bowden, G., Chambers, A., Spearman, M., et al. Secreted phosphoprotein mRNA is induced during multi-stage carcinogenesis in mouse skin and correlates with the metastatic potential of murine fibroblasts. Int. J. Cancer, 46: 133-137, 1990.
Hsu, S., Raine, L., and Fanger, H. Use of avidin-biotin peroxydase complex (ABC) in immunoperoxydase technique: a comparison between ABC, and unlabeled antibody (PAP) procedures. J. Histochem. Cytochem., 29: 577-580, 1981.
Mintz, K., Grzesik, W., Midura, R., Gehron Robey, P., et al. Purification and fragmentation of nondenaturated bone sialoprotein: evidence for a cryptic, RGD-resistant cell attachment domain. J. Bone Miner. Res., 8: 985-995, 1993.
Fisher, L.W., Hawkins, G.R., Tuross, N., and Termine, J.D. Purification and partial characterization of small proteoglycans I and II, bone sialoproteins I and II, and osteonectin from the mineral compartment of developing human bone. J Biol. Chem., 262: 9702-9708, 1987.
Fisher, L., McBride, W., Termine, J., and Young, M. Human bone sialoprotein: deduced protein sequence and chromosomal localization. J. Biol. Chem., 265: 23472351, 1990.
Bianco, P., Riminucci, M., Silvestrini, G., Bonucci, E., et al. Localization of bone sialoprotein (BSP) to golgi and post-golgi secretory structures in osteoblasts and to discrete sites in early bone matrix. J. Histochem. Cytochem., 41: 193-203, 1993.
Graham, C., and Karnovsky, M. The early stages of absorption of horseradish peroxidase in the proximal tubules of mouse kidneys: ultrastructural cytochemistry by a new technique. J. Histochem. Cytochem., 14: 291-390, 1966.
Fisher, L., Whitson, S., Avioli, L., and Termine, J. Matrix sialoprotein of developing bone. J. Biol. Chem., 258: 12723-12727, 1983.
Bianco, P., Fisher, L., Young, M., Termine, J., and Gehron Robey, P. Expression and localization of two small proteoglycans, biglycan and decorin, in human developing skeletal and non-skeletal tissues. J. Histochem. Cytochem., 38: 1549-1563, 1990.
Chen, J., Shapiro, S.S., Wrana, J.L., Reimers, S., et al. Localization of bone sialoprotein (BSP) expression to sites of mineralized tissue formation in fetal rat tissues by in situ hybridization. Matrix, 11: 133-143, 1991.
Maniatopoulos, C., Sodek, J., and Melcher, A. Bone formation in vitro by stromal cells obtained from marrow of young adult rats. Cell Tissue Res., 254: 317-330, 1988.
Oldberg, A., Jirskog-Hed, B., Axelsson, S., and Heinegard, D. Regulation of bone sialoprotein mRNA by steroid hormones. J. Cell Biol., 109: 3183-3186, 1989.
Oldberg, A., Franzen, A., Heinegard, D., Pierschbacher, M., and Ruoslahti, E. Identification of a bone sialoprotein receptor in osteosarcoma cells. J. Biol. Chem., 263: 19433-19436, 1988.
van der Pluijm, G., Kerr, J., Lowik, C., and Gehron Robey, P. β1 and β3 integrin subunits are involved in adhesion of breast cancer cells to extracellular bone matrix. J. Bone Miner. Res., 8 (Suppl): S136, 1993.
