Treatment of Breast Cancer Lytic Skeletal Metastasis Using a Model in Nude Rats

Cancer is a life-threatening disease, not as a result of the primary tumor that can be removed surgically in the vast majority of cases but from its metastatic spread to distant parts of the body. These metastases are often seen as a hopeless end-stage of the cancer disease and at this time only palliative treatments are applied. Some of the most prevalent solid tumors, such as breast-, lungand prostate cancers, metastasize into the skeleton and cause either osteolytic (destructive) or osteoblastic lesions. Both types are often accompanied by bone pain and increased bone fragility and thus are reason for extended suffering. In breast cancer, bone is the site of first distant relapse and the clinical course of these women is relatively long, with a median survival of 2-3 years (1, 2). Lytic skeletal metastases are present in over 90% of patients who die from breast cancer (3). Many factors are involved in the pathogenesis of lytic skeletal lesions among which the proteins osteopontin (OPN) and bone sialoprotein II (BSPII) are considered to play an important role. In patients with primary breast cancer, elevated serum BSPII was recognized as prognostic marker of subsequent bone metastasis and was associated with poor survival (4-8). BSPII is a noncollagenous protein of the extracellular bone matrix and a member of the SIBLING (Small Integrin-Binding Ligand, N-linked Glycoprotein) family. The SIBLINGs are mainly clustered on human chromosome 4, and include bone sialoprotein II, osteopontin, dentin matrix protein 1 (DMP1), matrix extracellular phosphoglycoprotein (MEPE) and dentin sialophosphoprotein (DSPP) (12). These proteins are normally expressed in mineralizing tissues of bone and teeth but are also found in different cancers (13). In normal bone, BSPII is expressed by osteoblasts, osteoclasts and other skeleton-associated cell types, especially at sites of new mineral formation (12, 14-16). In this case, BSPII is a potential nucleator of hydroxyapatite formation and a specific marker of osteoblast differentiation (14). The sialoprotein is involved in hydroxyapatite and collagen binding, as well as in the attachment of bone cells including fibroblasts, osteoblasts and osteoclasts to solid surfaces,